Non-HEU Production Technologies For Molybdenum-99 and Technetium-99m.

IAEA Nuclear Energy Series
Technical
Reports
Non-HEU Production
Technologies for
Molybdenum-99 and
Technetium-99m
No. NF-T-5.4
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INTERNATIONAL ATOMIC ENERGY AGENCY
VIENNA
ISBN 9789201377104
ISSN 19957807
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NON-HEU PRODUCTION TECHNOLOGIES
FOR MOLYBDENUM-99 AND
TECHNETIUM-99m
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NON-HEU PRODUCTION TECHNOLOGIES
FOR MOLYBDENUM-99 AND
TECHNETIUM-99m
IAEA NUCLEAR ENERGY SERIES No. NF-T-5.4
VIENNA, 2013
IAEA Library Cataloguing in Publication Data
Non-HEU production technologies for molybdenum-99 and technetium-99m.
Vienna : International Atomic Energy Agency, 2013.
p. ; 29 cm. (IAEA nuclear energy series, ISSN 19957807 ;
no. NF-T-5.4)
STI/PUB/1589
ISBN 9789201377104
Includes bibliographical references.
1. Molybdenum Isotopes. 2. Technetium Isotopes. 3. Radionuclide
generators. I. International Atomic Energy Agency. II. Series.
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CONTENTS
1. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1. Background. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2. Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.3. Scope. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
1.4. Intended audience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
1.5. Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. PRODUCTION OF
99
Mo/
99m
Tc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3. ORGANIZATION OF PRODUCTION TECHNOLOGIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
4. REACTOR BASED PRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
4.1. Fission based (n, f) production in heterogeneous reactors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
4.1.1. Targets and processing methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
4.1.2. Waste. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
4.1.3. Regulatory issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
4.2. Fission based (n, f) production in homogeneous reactors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
4.2.1. Fuel/target solutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
4.2.2. Waste. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
4.3. Neutron activation production (n, ) in heterogeneous reactors . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
4.3.1. Targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
4.3.2. Waste. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
5. ACCELERATOR BASED PRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
5.1. Fission based (n, f) production using accelerators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
5.1.1. Proton accelerator production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
5.1.2. Deuteron accelerators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
5.1.3. Subcritical liquid LEU target for accelerator driven production of fission
99
Mo. . . . . . . . . 16
5.2. Photon based (, n) production using electron accelerators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
5.2.1. Target materials. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
5.2.2. Recycling of target materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
5.2.3. Waste. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
5.3. Neutron induced process
100
Mo(n,2n)
99
Mo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
5.3.2. Recycling of target materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
5.3.3. Waste. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
5.4. Direct production of
99m
Tc using proton accelerators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
5.4.2.
99m
Tc pertechnetate yields and purity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
5.4.3. Waste. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
6.
99
Mo/
99m
Tc GENERATOR SYSTEMS AND CHEMISTRY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
6.1. High specific activity (fission product) generators. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
6.1.1. Principles of generator operation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
6.1.2. Chemistry of alumina column based generator and technetium cows . . . . . . . . . . . . . . . . . 25
6.2. Low specific activity
99
Mo/
99m
Tc recovery methods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
6.2.1. Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
6.2.2. Liquidliquid generator concept . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
6.2.3. Low cost/high efficiency wet extraction using an automated unit . . . . . . . . . . . . . . . . . . . . 27
6.2.4. Post-production isotopic separation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
6.2.5. Solvent extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
6.2.6. Sublimation extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
6.2.7. Post-elution concentrator . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
6.3. Low specific activity generator types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
6.3.1. Technetium selective separation system. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
6.3.2. Jumbo alumina column generator . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
6.3.3. Gel moly generator . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
6.3.4. High adsorption capacity column generator . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
6.3.5. Technetium radiolabelling. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
7. TECHNOLOGY READINESS TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
7.1. Reactor based technologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
7.2. Accelerator based technologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
8. CONCLUSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
APPENDIX A: TECHNOLOGY READINESS LEVELS (TRLs) AND THEIR DEFINITIONS. . . . . . . . . . 43
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
GLOSSARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
ABBREVIATIONS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
CONTRIBUTORS TO DRAFTING AND REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
1
1. INTRODUCTION
1.1. BACKGROUND
Technetium-99m (
99m
Tc) is used in approximately 85% of nuclear medicine diagnostic imaging procedures
worldwide. Almost all the
99m
Tc used for this purpose is obtained from the radioactive decay of molybdenum-99
(
99
Mo), which is produced by processing irradiated uranium targets in Belgium (IRE), Canada (AECL/Nordion),
the Netherlands (Covidien) and South Africa (NTP). After irradiation, the uranium targets are processed to extract
99
Mo, which in turn is purified for use in
99
Mo/
99m
Tc generators that are shipped to radiopharmacies, hospitals and
clinics. Demographic and medical trends suggest that, at least in the near future, global demand for
99m
Tc will grow
at an average annual rate of 38% as these diagnostic imaging procedures expand to new markets, such as those in
Asia [1].
The research reactors used to irradiate targets that produce most of the worlds supply of
99
Mo are over
40 years old. Planned and unplanned shutdowns of some of these reactors have resulted in several recent
99
Mo/
99m
Tc supply interruptions. These interruptions prompted international organizations and several government
agencies to step up efforts to find both short and long term solutions to supply shortages. In response to a Canadian
government initiative, the OECD/NEA established the High Level Group on the Security of Supply of Medical
Radioisotopes (HLG-MR) with participation by the IAEA as an observer. Several Member States of the IAEA
expressed concern about supply shortages during the 2009, 2010 and 2011 Board of Governors Meetings and IAEA
General Conferences (GC). The 2009 Conference, in Resolution GC(53)/RES13, urged the Secretariat to work
cooperatively with other international initiatives ... to implement activities that will contribute to enhancing the
molybdenum-99 production capacity, including in developing countries, in an effort to ensure the security of
supplies of

molybdenum-99 to users worldwide. These calls for action continued throughout 2012 in the work of
the OECD and IAEA. In support of these efforts, the OECD published economic and technology studies on the
99
Mo supply chain [2, 3].
The IAEA convened a group of experts to initiate a new activity specifically aimed at supporting global
efforts to improve
99
Mo/
99m
Tc supply reliability and promoting the conversion of
99
Mo

production from highly
enriched uranium (HEU) to low enriched uranium (LEU). Three of the four facilities used to produce most of the
worlds supply of
99
Mo use HEU targets with
235
U enrichments of up to 93%. The remaining producer, NTP in
South Africa, produces
99
Mo using 19.75% LEU and 45% HEU. Plans for converting South African production to
LEU reached a major milestone in 2010 when LEU based
99
Mo

was imported into the United States of America for
use in patients. The Australian Nuclear Science and Technology Organization is routinely producing
99
Mo

from
LEU targets irradiated in the OPAL reactor. Efforts continue to ramp up production there.
The IAEAs focus on the conversion of
99
Mo production from HEU to LEU is part of a long standing effort to
eliminate HEU use in civilian applications. This effort received a boost in 2009 when the US National Academy of
Sciences concluded that the elimination of HEU in medical isotope production is technically and economically
feasible [4]. The scope of all IAEA activities related to improving
99
Mo/
99m
Tc supplies, including this publication,
supports global efforts to eliminate the civilian use of HEU.
The reliability of
99
Mo/
99m
Tc supply can be improved by increasing diversity and redundancy in all aspects of
the supply chain. Smaller scale production (for domestic and regional use) and well distributed production facilities
are important supplements for increasing supply reliability. Several alternative/supplementary technologies for
producing
99
Mo/
99m
Tc have been proposed. Some of them are not yet commercially proven and some are still in the
early stages of development. International exchanges of information can hasten the development of technically and
economically viable technologies and prepare them for deployment.
1.2. OBJECTIVES
The objectives of this report are to document current and novel
99
Mo/
99m
Tc production technologies that do
not involve the use of HEU and thereby facilitate international cooperation on
99
Mo

supply and technology
2
development. These technologies were compiled from information provided by consultants and participating
Member States.
This report complements other related IAEA and international activities. They include the IAEA coordinated
research project (CRP) on Small Scale Indigenous
99
Mo

Production (2005 to 2011), a CRP on Accelerator Based
Alternatives to Non-HEU Production of
99
Mo/
99m
Tc, the Peaceful Uses Initiative (PUI) and technical cooperation
projects on small scale
99
Mo production technology deployment, as well as robust studies, conducted, for example,
in Canada, Europe, the USA and by the OECD/NEA [2, 3].
1.3. SCOPE
This report considers current and novel non-HEU
99
Mo/
99m
Tc production technologies at all stages of the
production process and on all scales (local to global) of supply. It considers improvements to existing technologies
for producing
99
Mo

involving fission and neutron activation, novel technologies for producing
99
Mo such as
photofission and transmutation as well as technologies for the direct production of
99m
Tc. This report considers
technologies at all stages of development. This approach ensured the most comprehensive review of existing and
novel
99
Mo/
99m
Tc technologies.
The focus of this report is on the technical readiness of
99
Mo/
99m
Tc production technologies. Efforts to
compile the report did not consider non-technical or business related issues such as manufacturing readiness, cost,
supply demand or supply security. Although all of the production technologies considered in this report produce
waste by-products, such production is a result of the application of a technology and not an attribute of technology
development. The report does not consider specific waste management technologies. However, the expected waste
and regulatory requirements associated with the different technologies are discussed.
1.4. INTENDED AUDIENCE
The IAEA cooperated with other international organizations including the HLG-MR of the OECD/NEA
and with Member States throughout the supply crises and the project to produce this report. Specifically, the
IAEA encouraged partnerships, cooperation and complementary implementation of
99
Mo/
99m
Tc production and
supply technologies among interested governmental, scientific and technical organizations. To achieve this end, this
report has been developed for policy and decision makers within these governmental, scientific and technical
organizations.
1.5. STRUCTURE
This report is broken into eight major sections and includes one appendix. The first three sections introduce
the subject, provide background information on
99
Mo production and lay out the technical breakdown of the
remaining discussion.
Section 4 discusses reactor based
99
Mo production. In general, this includes fission of heterogeneous uranium
targets, fission of homogeneous uranium solution and activation of natural and enriched
98
Mo targets. The section
also describes technologies to address low specific activity
99
Mo, a challenge specific to
98
Mo activation based
production.
Section 5 considers accelerator based
99
Mo/
99m
Tc production. Both fission and non-fission production
technologies are described, as are target materials, chemistry, waste and post-production isotopic separation.
Accelerator based production is receiving significant interest and investment, but remains in the development
phase.
Section 6 describes
99
Mo/
99m
Tc generator systems. Generator technology is an important aspect of the
99m
Tc
supply chain. However, a given technology could apply to both reactor and accelerator based technologies.
Therefore generator technology is considered in a separate section.
3
Section 7 includes technology readiness tables for technologies presented in sections 3 and 4. Generator
technology is included within individual production methods. The tables reflect the outcome of an objective,
evidence based review of the different production technologies.
Section 8 includes the conclusion. An appendix explains the technology readiness terminology beyond what
was presented in Section 3. This is followed by a list of references, a glossary and a list of longhand terminology
abbreviated throughout the report.
2. PRODUCTION OF
99
Mo/
99m
Tc
Molybdenum-99 is a radioactive isotope that undergoes beta decay with about a 66 hour half-life (Fig. 1).
About 88% of these decays result in the production of the metastable isotope
99m
Tc (Fig. 1), which subsequently
decays to the ground state (
99g
Tc) with about a 6 hour half-life.
The present gold standard process for producing
99
Mo for medical isotope use involves the neutron fission
of
235
U (i.e.
235
U(n,f)
99
Mo) in multipurpose research reactors (Fig. 2). About 6.1% of the
235
U fissions produce
99
Mo. The cross-section for this reaction is large (~584 barns for thermal neutrons) compared with other production
processes shown in Fig. 2. Multipurpose research reactors are especially well suited for
99
Mo production because
they have space for irradiating multiple targets at high neutron fluence rates (typically in the order of
10
13
10
14
neutrons per square centimetre per second (ncm
2
s
1
)).
Molybdenum-99 can be produced through a number of other schemes illustrated in Fig. 2:
Fission of
235
U with neutrons produced in deuteron and proton accelerators through (D, n) and (p, n) reactions
on heavy targets.
Neutron activation of
98
Mo (i.e.
98
Mo(n,)
99
Mo). This process is only practical for reactor based production
owing to the small activation cross-section (0.13 b for thermal neutrons). Also,
99
Mo produced through this
process has a lower specific activity than neutron fission produced
99
Mo.
Photofission of
100
Mo (i.e.
100
Mo(,n)
99
Mo). The energetic photons used in this production scheme are
obtained by irradiating heavy targets with electron beams produced by linear accelerators.
FIG. 1.
99
Mo decay.
4
Technetium-99m can also be produced directly through (p, 2n) reactions on targets containing
98
Mo (Fig. 2).
This production scheme eliminates the need for intermediate production steps involving the recovery and
purification of
99
Mo. However, it is suitable only for short (e.g. city scale) supply chains because of the short
half-life of
99m
Tc.
All the production schemes shown in Fig. 2 result in the production of by-product wastes. The major waste
streams include off-gas generated during target processing and liquid and solid processing residues. Some key
waste production characteristics for each production scheme are described in this report.
3. ORGANIZATION OF PRODUCTION TECHNOLOGIES
The discussion of
99
Mo/
99m
Tc production technologies in this report is organized according to the production
schemes shown in Fig. 2. Section 4 describes reactor based production schemes and Section 5 describes accelerator
based production schemes. The following information is provided for each production scheme shown in Fig. 2:
Description of the production scheme;
Target materials and processing;
Waste;
Regulatory issues.

Reactors
Accelerators
Heterogeneous
Homogeneous
Electron
Deuteron
Proton
235
U
98
Mo
235
U
235
U
235
U
100
Mo
98
Mo
e,
target
D,n
target
p,n
target
n,f
n,
n,f
,n
n,f
n,f
p,2n
99
Mo
99
Mo
99m
Tc
100
Mo n,2n
FIG. 2. Schemes for producing
99
Mo and
99m
Tc discussed in this report.
5
Section 6 describes technologies for concentrating and storing
99
Mo/
99m
Tc produced from both reactor and
accelerator based technologies.
Tables 614, which are included at the end of this report, provide estimates of technology readiness level
(TRL) for each of the production schemes. Judgements on TRL were based on information supplied by technology
developers, information available from the literature and also from extrapolations from other technologies. With
respect to extrapolation, one can assume, for example, that processes for isolating
99
Mo

from a uranium target will
be similar regardless of whether the target was irradiated in a reactor or an accelerator. The TRLs shown in the
tables are not judgements about the ability of any particular technology developers to implement a particular
technology. In fact, implementation of any particular technology could require assistance from experienced
technology developers and may entail the use of proprietary information.
4. REACTOR BASED PRODUCTION
4.1. FISSION BASED (n, f) PRODUCTION IN HETEROGENEOUS REACTORS
At present, most of the worlds supply of
99
Mo for medical diagnostic imaging is produced by irradiating solid
targets containing
235
U in heterogeneous reactors. After irradiation in the reactor, the target is digested in acid or
alkaline solutions and
99
Mo is recovered through a series of extraction (separation) and purification steps.
As noted in Section 1, most current
99
Mo production utilizes targets containing HEU. However, LEU targets
have been developed and are currently being used for small to medium scale
1
commercial
99
Mo production by
several organizations:
(1) Targets containing uranium-aluminium dispersed in an aluminium matrix (commonly referred to as UAl
2
or
UAL
x
targets). The dispersion is clad between thin (nominally 0.3 mm) aluminium plates. These targets are
currently being used by CNEA, ANSTO and NECSA
2
to produce
99
Mo. This target is described more fully in
Section 4.1.1.1.
(2) Targets containing uranium metal foil. The foil is clad between aluminium tubes and is separated from the
cladding by a recoil barrier; the barrier prevents the foil from bonding to the cladding. These targets have been
successfully irradiated and processed on a trial basis at BATAN, CNEA and MURR [3]. This target is
described more fully in Section 4.1.1.4.
A 2009 report from the USA National Academy of Sciences concluded that LEU targets that could be used for
large scale production of
99
Mo have been developed and demonstrated. The expert committee that authored this
report also concluded that it saw no technical reasons that adequate quantities (of
99
Mo) cannot be produced from
LEU targets in the future [4]. While the present IAEA report was being developed, ANSTO demonstrated large
scale production of
99
Mo, although it has not yet implemented routine production on a large scale.
The following sections describe LEU target materials and processing methods that could potentially be used
for the production of
99
Mo on small to large scales.
1
NECSA has reported that production will be increased following non-nuclear regulatory approvals in customer countries.
2
NECSA successfully demonstrated their capability to produce
99
Mo from LEU targets in 2010. As of the final edit of this
report, NECSA was continuing to work toward routine production and a complete process conversion to LEU.
6
4.1.1. Targets and processing methods
4.1.1.1. UAl
x
dispersion targets
Uranium-aluminium (UAl
x
) dispersion targets comprised of HEU and LEU are currently being used to
produce
99
Mo worldwide. These targets are manufactured to MTR fuel specifications by both CERCA and CNEA
and are qualified to moderate burnup (i.e. >30%). This burnup is typically several times greater than that
experienced during target irradiation for
99
Mo production. Historically, multiple thousands of HEU dispersion
targets have been safely irradiated and processed to produce
99
Mo of high quality and purity.
The uranium density (also referred as uranium loading) of an LEU dispersion target is in the range of
2.53.0 gU/cm
3
. In contrast, the maximum uranium density of HEU dispersion targets now in use is s1.6 gU/cm
3
.
In comparison, uranium metal targets have a density of 19.0 g/cm
3
. An LEU dispersion target manufactured by
CNEA is shown in Fig. 3.
LEU Al
x
dispersion targets are currently being irradiated on a routine basis to produce
99
Mo in Argentina,
Australia and South Africa. Both Covidien and IRE currently use HEU Al
x
dispersion targets manufactured by
CERCA to produce
99
Mo. CERCA is currently manufacturing LEU Al
x
dispersion targets for NECSA. ANSTO has
used LEU Al
x
dispersion targets supplied by both CERCA and CNEA.
LEU dispersion target fabrication begins with LEU UAl
2
particles matrixed with pure aluminium powder. The
UAl
2
to UAl
3
/UAl
4
phase transformation is inherent to the fabrication process used to manufacture these targets.
(The various steps of the fabrication process convert UAl
2
to UAl
3
/UAl
4
.) The ratio of UAl
3
to UAl
4
in a finished
target will vary from manufacturer to manufacturer depending on the processes and heat treatments that are used in
fabricating the powder, core compacts and target plates [6].
All current
99
Mo producers who use LEU Al
x
targets use an alkaline digestion chemical process. Multiple
targets are digested in a dissolver unit containing sodium hydroxide (NaOH), or, in the case of IRE and PINSTECH,
NaOH and NaNO
3
. The molybdenum in the dissolution liquor is then recovered and purified by a series of
processing steps. The number of purification steps, typically four or five, varies from producer to producer. The
process used by both Covidien and CNEA and subsequently marketed by the GammaService Group International
(GSG) and INVAP is based on technology developed by A.A. Sameh at KfK [79]. The alkaline digestion based
chemical processing scheme for LEU Al
x
dispersion targets has been successfully demonstrated with LEU targets
in Australia, Argentina and South Africa.
GSG is also marketing a chemical digestion processes called ROMOL99 [10]. The process involves the
dissolution of UAl
x
dispersion targets in a closed system under reduced pressure conditions (and without generation
FIG. 3. CNEAs LEU-aluminium dispersion targets. These targets have been used since 2002 to produce
99
Mo in Argentina. The target
is 13.0 cm in length and 3.5 cm in width [5].
7
of H
2
) including a NH
3-
and iodine removal process step. The process is being operated using semiautomated
process control. This process is currently being used with HEU targets by PINSTECH and in Dimitrovgrad
(Russian Federation) with a production capacity of 200250 6 day Ci (74009250 GBq).
4.1.1.2. U
3
Si
2
-Al dispersion targets
U
3
Si
2
has been successfully used as research reactor fuel for many years. This fuel is manufactured to
established and industry accepted MTR fuel specifications [11]. It has been qualified to a uranium loading of
4.8 g/cm
3
for research reactors [12]. For use as a
99
Mo production target, a uranium loading of 6.0 g/cm
3
is
achievable [13].
In October 1988 the US Nuclear Regulatory Commission (NRC) approved the use of U
3
Si
2
-Al dispersion fuel
in its licensed plate type reactors at densities of up to 4.8 gU/cm
3
and up to power densities and
235
U burnup values
typical of fuels tested in the 30 MW Oak Ridge Research Reactor at the Oak Ridge National Laboratory. Since that
time regulatory authorities in many other countries have approved the use of U
3
Si
2
-Al plate type fuel.
The French research reactor fuel fabricator (CERCA) announced in 1992 that it could provide U
3
Si
2
-Al
dispersion fuels up to a density of 6.0 gU/cm
3
[14]. Five fuel plates with uranium densities of 5.8 and
6.0 gU/cm
3
were irradiated at the Silo reactor in Grenoble, France, to a burnup of 55% in 1995 to 1997 and two
5.8 gU/cm
3
fuel assemblies were irradiated in Osiris to a burnup of 74% in 1997 and 1998. These irradiations
produced very good results [13].
These manufacturing developments and irradiations have shown that higher density U
3
Si
2
-Al dispersion fuel
can be manufactured reliably and perform well under irradiation. By the definition of qualified fuel presented in
Ref. [15], 6.0 gU/cm
3
U
3
Si
2
-Al dispersion fuel can be considered to be qualified for use under conditions that do not
exceed those of the test irradiations described above.
Uranium silicide-aluminium (U
3
Si
2
) dispersion targets have been evaluated for use to produce
99
Mo [16].
Dissolution of 4.8 gU/cm
3
U
3
Si
2
-Al targets by a process has been demonstrated on a laboratory scale. The
mechanism and rates for dissolution of the aluminium cladding, aluminium in the fuel matrix and the silicide
particles are understood. Irradiated silicide has a slow dissolution rate owing to the bonding of silicide particles
during irradiation. A chemical method to break up the fused silicide particles before or during dissolution is
required to successfully process these targets.
The use of alloyed aluminium cladding (e.g. Al type 6061) necessitates a solids separation step following
cladding dissolution. Hydroxide precipitates of alloying elements are suspended in the spent cladding dissolver
solution. Separation of this low density precipitate from the high density U
3
Si
2
is possible.
U
3
Si
2
cannot be readily dissolved by sodium hydroxide (NaOH) solutions or NaOH solutions containing
sodium nitrate (NaNO
3
). Therefore, the cladding and aluminium powder in the fuel matrix are dissolved in one step
using potassium hydroxide (KOH) and a second step is required using a more powerful reagent, such as
hydrofluoric acid, to dissolve the U
3
Si
2
. Because some of the
99
Mo is lost to the aluminium matrix due to fission
recoil, it must be recovered during both dissolution steps to maximize the
99
Mo yield of a production batch.
The dissolution and chemical processing of a U
3
Si
2
target containing greater than 4.8 gU/cm
3
has not yet been
demonstrated.
GSG is marketing a further developed version of this process as the Karlsruhe Sameh Silicide (KSS) process.
4.1.1.3. Uranium nitride (UN) dispersion targets
Uranium nitride MTR fuel plates have been developed and fabricated on a laboratory scale [17]. Uranium
nitrides are denser, more stable and conduct heat better than mixed uraniumplutonium oxide reactor fuels
properties that suggest these fuels could run cooler in power reactors to generate more thermal energy.
In the mid-1980s, a method to create a discrete compound of uranium nitride was discovered. The compound
is uranium nitrid important because its ceramic state, uranium mononitride, was identified as a candidate for reactor
nuclear fuel.
Published reactor fuel characteristics, for alloy in an aluminium matrix, identify the uranium loading of the
dispersed phase as approximately 13.5 g/cm
3
. When fabricated to the requirements of MTR fuel specifications, the
maximum uranium loading of a UN fuel plate (or target) is 7.0 g/cm
3
.
8
4.1.1.4. Uranium foil targets
Argonne has developed an LEU foil target for
99
Mo production (Fig. 4). The uranium loading of the LEU foil
is approximately 19 g/cm
3
. This is much higher than the uranium loading of HEU or LEU dispersion targets, which
typically contain no more than 1.6 gU/cm
3
and between 2.5 and 3.0 g U/cm
3
, respectively, as noted previously.
The target consists of a thin (typically 100150 m thick) uranium foil sandwiched between 15 m thick
nickel or 40 m thick aluminium fission recoil barriers. The foil barrier sandwich is contained in a tubular
aluminium cladding. The fission barrier prevents the LEU foil from bonding with the aluminium cladding during
irradiation.
After irradiation, the foil is removed from the aluminium cladding for chemical processing and the cladding
is discarded as low activity solid waste. The removal of the foil from the cladding prior to chemical processing
reduces the processing time and the volume of processing waste compared to LEU dispersion targets. The target has
been chemically processed using the LEU Modified Cintichem process developed by Argonne, which involves
dissolution in nitric acid (HNO
3
).
LEU foil targets have a limited irradiation history. Targets have been successfully irradiated in Argentina,
Indonesia, Australia and the USA. Approximately thirty LEU foil targets have been irradiated worldwide to date.
Furthermore, LEU foil targets are not currently manufactured to an industry accepted standard or
specification. Such a standard or specification must be developed and a corresponding target qualification
programme must be implemented before this target can be adopted for widespread use.
Additionally, LEU foil targets have not been industrially adapted to the alkaline target dissolution processes
used by many current
99
Mo producers. Argonne has developed two front end options for using LEU foil targets in
alkaline based processes for use with these targets. It is anticipated that they will be demonstrated on a production
scale in 2013 [18].
A small scale
99
Mo producer (BATAN in Indonesia) planned to convert to LEU foil targets after exhausting its
inventory of HEU. (At the time of this report, BATAN was not producing LEU foil target based
99
Mo.)
Consequently, for small scale
99
Mo production, target fabrication and chemical processing of LEU foil targets is not
yet fully mature.
Work is in progress by the University of Missouri, Argonne and B&W Y-12 to develop LEU foil annular
target specifications, a manufacturing method for high volume target production and quality control test criteria [19,
20]. Work is also in progress to transition the annular design to a plate (flat or curved) geometry as an option [21,
22]. Thin uranium metal foils manufactured by B&W Y-12 and KAERI are shown in Figs 5 and 6, respectively.
FIG. 4. LEU foil annular target comparison to a typical HEU dispersion target. Annular target shown with nickel wrapped 24 gU
(LEU)
foil exposed. A typical HEU dispersion target contains ~5 gU
(HEU)
. Both targets yield about the same activity of
99
Mo if irradiated with
the same thermal neutron flux and irradiation time.
9
4.1.1.5. Uranium metal targets
The concept of uranium metal targets is by no means new. Natural uranium metal slugs electroplated with
nickel (~7 m in thickness) and clad in aluminium (1.27 mm in thickness) were used to produce plutonium in the
Savannah River reactors [23]. Thousands of these slugs were routinely irradiated and chemically processed over a
period of about fifty years.
CINR Rossendorf routinely irradiated and processed natural uranium metal pellet targets to produce
99
Mo
from 19631980 [24]. The target material was dissolved in HCl and
99
Mo was separated from the dissolution liquor
using an alumina column. Commercially available 5% enriched uranium metal in the form of pellets, disks or strips
could be used in lieu of natural uranium target material for
99
Mo production. GSG developed a processing system
concept, LITEMOL, which aims to provide a small scale
99
Mo production capability to those institutions operating
research reactors with moderate neutron flux densities (15 10
13
). The chemistry of the LITEMOL concept is
identical to that used at CINR. However, this processing concept has not yet been demonstrated using the
commercially available 5% enriched uranium metal disks or strips.
4.1.1.6. Uranium oxide (UO
2
) targets
ANSTO routinely irradiated 1.8% enriched UO
2
pellets to produce
99
Mo in the early 1980s. The enrichment
of the pellets was later increased to 2.2%. The density of UO
2
in a dispersed phase was approximately 9.7 g/cm
3
.
The pellets were irradiated for up to 7 days in a double encapsulated aluminium can configuration. The small gap
between the fuel pellets and the aluminium irradiation can was filled with magnesium oxide (MgO) to enhance heat
dissipation.
Following irradiation, the pellets were separated from the MgO powder by sieving, followed by dissolution in
concentrated nitric acid.

The solution was passed through an alumina column, which sorbed the
99
Mo. The
remainder of the solution, which contained uranium and most of the fission products, passed through the column.
The alumina column was then washed in sequence with nitric acid, purified water and a dilute ammonia solution to
remove traces of contaminants.
The purified
99
Mo was eluted from the column with concentrated ammonia solution, followed by boiling the
solution to remove residual traces of iodine and ruthenium. The alumina column separation was repeated to produce
99
Mo of the specified purity [25].
The EOB yield of a target batch was approximately 135 Ci (5,000 GBq). Up to five production runs were
performed on a weekly basis, totalling 675 Ci (25,000 GBq) at EOB. Technetium-99m generator production was
spread out over the entire week. ANSTO continued to produce
99
Mo using the UO
2
pellets until late 2006, when it
began transitioning to LEU UAl
x
targets.
FIG. 5. Uranium metal foil fabricated on a trial basis by
B&W Y-12. The thickness of the foil is ~115 m.
FIG. 6. Uranium metal foil fabricated by KAERI using their
cooling roll casting method. The average thickness of the foil is
~140 m.
10
JAERI also produced
99
Mo in 1977 using UO
2
pellets (2.6% enrichment) as a target material. JAERI
irradiated 120 g of pellets in the JRR-2 or JRR-3 reactor for up to 7 days at a maximum neutron flux of
3 10
10
ncm
2
s
2
. A batch of about 20 Ci (740 GBq) of
99
Mo per week was routinely shipped to a local
99
Tc
generator manufacturer [26].
AECL designed an HEU UO
2
powder annular target for irradiation in the MAPLE reactors. The UO
2
powder
was vibra-packed between two concentric cylinders made from zirconium and hot isostatic pressed to seal the target
and provide good thermal contact between the target meat and cladding. These targets were fabricated by B&W but
were never used.
From the early 1970s to 1989, the Cintichem reactor facility prepared targets using HEU electroplated from a
uranyl oxalate system onto the inside surface of a stainless steel tube [27]. After electroplating, the tubes were
heated to convert the uranium to UO
2
and their tops and bottoms were welded shut. After irradiation, the tubes
served as dissolver vessels.
4.1.1.7. Uranium aluminide alloy targets
The target is fabricated from UAl alloy rods clad with aluminium. This target is manufactured by AECL
using HEU and is of the same basic construction as the HEU fuel rods that were used in the NRU reactor before its
conversion.
LEU based targets of the same general design and dimensions would yield less
99
Mo activity than the HEU
targets they replace. The amount of decrease would depend on the density of
235
U in the LEU target compared to the
HEU target.
4.1.1.8. Uranium metal particle aluminium matrix dispersion targets
This target design is being developed by KAERI. An atomization process produces 50150 m uniform
spherical uranium metal particles, which are incorporated into an aluminium metal matrix to produce the target
meat. A uranium volume fraction is anticipated of up to 50% (approximately 9.0 gU/cm
3
) in the target meat with
these small particle sizes.
Small amounts of silicon, chromium, iron or other elements can be alloyed with the uranium metal and/or a
small amount of silicon can be alloyed with the pure aluminium matrix to retard the interaction with uranium metal
particles [28].
4.1.2. Waste
Uranium fission production schemes generate higher volume and activity waste compared with other
production schemes described in this report. Uranium fission production also requires substantially higher shielding
for targets, processing and waste handling. The liquid processing wastes must be solidified and stored until a
permanent disposal pathway becomes available.
Production of
99
Mo using LEU targets will generate waste with the same characteristics as that produced from
HEU targets. However, waste volumes could be different (larger or smaller) depending on target design.
4.1.3. Regulatory issues
Regulatory approvals will be needed before new target designs can be irradiated on a routine basis and also
before
99
Mo produced from these targets can be used in medical procedures.
The safety aspects of target use are evaluated in a manner consistent with the evaluation of reactor fuel.
Thermohydraulic considerations will dictate the maximum thermal power (kW) of the targets, their uranium mass
and the requirements for their positioning in the reactor. Also, a target failure in containment analyses must be
performed as part of the safety case for target irradiation. Historically, targets fabricated from the same material as
the reactor fuel material have been easiest to qualify and license. The safety aspects of target processing must also
be addressed.
The production of
99
Mo using LEU targets is almost identical to the present gold standard process for
producing
99
Mo using HEU, and chemical processing is in many cases almost identical. In some cases, however,
11
chemical processing might have to be modified to accommodate larger masses of LEU target material. The LEU
based production process and products will have to be validated and approved by regulatory bodies, but past
experience suggests that this will be a straightforward process when carried out in close coordination with
regulators.
4.2. FISSION BASED (n, f) PRODUCTION IN HOMOGENEOUS REACTORS
A pseudo-prototype system,
99
Mo production and recovery from an aqueous homogeneous reactor (ARGUS),
has been demonstrated on a pilot scale in the Russian Federation. The Kurchatov Institute, in collaboration with
Argonne and Technology Commercialization International, a private company from the USA that is no longer in
business, developed an LEU uranyl sulphate based aqueous homogeneous reactor at ARGUS to produce
99
Mo. The
concept never progressed beyond laboratory scale development, but a similar concept is now being pursued by
CJSC Resources and Technologies [29] and ROSATOM.
Babcock and Wilcox has developed a conceptual design for a 200 kW aqueous homogeneous reactor and
recovery system to produce
99
Mo, called MIPS. The reactor fuel solution, which contains LEU salt dissolved in
water and acid, is also the target material for
99
Mo production. The reactor would be operated to allow the buildup
of
99
Mo in the fuel solution. The reactor would then be shut down and the fuel solution pumped through a recovery
column that preferentially sorbs molybdenum. Molybdenum-99 would be recovered by stripping (i.e. eluting) the
recovery column and subsequently conditioned by one or more purification steps.
Babcock and Wilcox estimate that a single 200 kW MIPS is capable of producing about 10 000 Ci
(370 000 GBq) of
99
Mo at the EOB (5 day irradiation). The expected yield from sorbent extraction is 90%.
Assuming a 10 hour processing time, approximately 8000 Ci (~1700 6 day Ci) (296 000 GBq or ~62 900 6 day
GBq) can be produced on a weekly basis
3
. A comprehensive description of the MIPS concept is presented in
IAEA-TECDOC-1065 [30].
A key technical challenge in utilizing solution reactor technology for the production of
99
Mo is the
development of an efficient method for extracting or separating the product isotope from the irradiated fuel
solution. Specifically, the effects of radiation and fission product buildup on the separation of
99
Mo by an adsorbent
media must be determined. Several different adsorbent media have been evaluated: Termoxid 52 (T52), Termoxid
5M (T5M), titanium dioxide (TiO
2
) and alumina (Al
2
O
3
) [31]. Because of the relatively high uranium nitrate or
uranium sulphate concentration of the fuel solution, alumina has insufficient sorption properties for use in the
molybdenum recovery system.
4.2.1. Fuel/target solutions
Two types of aqueous fuel solutions have been considered for
99
Mo production using an AHR: (1) uranium
nitrate [UO
2
(NO
3
)
2
] and (2) uranium sulphate [UO
2
SO
4
]. Some characteristics of these solutions are described in
the following sections.
4.2.1.1. Uranyl nitrate fuel solution
Uranyl-nitrate solutions have superior chemical properties for the separation of Mo and for waste treatment
relative to uranyl-sulphate solutions. However, the radiolytic decomposition of an aqueous uranyl-nitrate solution is
far more complex than that of the sulphate salt. In addition to the radiolysis production of H
2
and O
2
from water,
nitrate is reduced forming nitrite, nitrogen and nitrogen oxide (NO
x
) gases and ammonium ions are also generated
from the radiolytic decomposition of the fuel solution. A subsystem to remove the NO
x
gases may be required in the
design of the off-gas system to prevent degradation of the charcoal filters (if charcoal is chosen as a sorbent for
fission gas removal).
3
This information was reported by Babcock and Wilcox in a
99
Mo production R&D survey submitted to the IAEA.
12
4.2.1.2. Uranyl sulphate fuel solution
Uranyl sulphates main advantage is that only H
2
and O
2
are formed by the radiolytic decomposition of the
fuel solution. These gases can be recombined to water using a catalyst bed (recombiner) and the condensed water
can then be returned to the fuel solution. Its disadvantages are related to the chemistry of sulphate and its salts. This
is the concept pursued by the Kruchatov Institute at the ARGUS reactor.
4.2.2. Waste
The operation of homogeneous reactors will produce off-gas wastes and liquid waste streams, primarily the
reactor fuel/target and process wastes from
99
Mo purification steps. The reactor fuel/target solutions will have to be
periodically replaced or replenished. The waste will have to be solidified and stored until a disposal pathway
becomes available.
Regulatory concern is expected to focus on the stated subcritical nature of the system and design features that
will assure that it will remain subcritical. There may also be regulatory issues regarding the disposition of process
wastes from these systems.
Over time, fission products will accumulate in the solution as discussed above. Changes to the solution may
have to be addressed to satisfy non-nuclear/pharmacoepeia regulatory requirements.
4.3. NEUTRON ACTIVATION PRODUCTION (n, ) IN HETEROGENEOUS REACTORS
Neutron activation based
99
Mo production (i.e.
98
Mo (n, )
99
Mo) is a viable and proven technology that dates
back to the 1960s. As an example, MURR began producing low specific activity neutron activation for the USA by
irradiating pressed sintered metal natural
98
Mo targets in 1967. MURR continued producing
99
Mo by this method
into the early 1980s. Production was suspended because neutron capture based
99
Mo could not compete
economically with the high specific activity fission product
99
Mo produced domestically at the Cintichem reactor
facility (see Section 4.1.1.6).
The production of neutron activation based
99
Mo is being carried out in several countries on a routine basis,
including India, Japan, Kazakhstan, Peru, the Russian Federation and Uzbekistan.
4.3.1. Targets
Several types of
98
Mo target can be used to produce
99
Mo through the (n, ) scheme. These are described in the
following sections.
4.3.1.1. Molybdenum metal/molybdenum trioxide (MoO
3
) powder
There are 35 known isotopes of molybdenum, 7 of which occur naturally with atomic masses of 92, 94, 95,
96, 97, 98 and 100. Of these naturally occurring isotopes, 6 are stable, with atomic masses from 92 to 98.
Molybdenum-100 is the only naturally occurring isotope that is not stable. Molybdenum-100 has a half-life of
approximately 8.0 10
18
years and undergoes double beta decay into
100
Ru. All unstable isotopes of molybdenum
decay into isotopes of niobium (Nb), technetium (Tc) and ruthenium (Ru). Molybdenum-98 is the most common
isotope, comprising 24.1% (natural abundance) of all molybdenum on Earth. In comparison, the natural abundance
of
100
Mo is only 9.6%.
High specific activity
99
Mo cannot be produced using natural Mo targets because the thermal neutron cross-
section for
98
Mo neutron capture reaction (n, ) is only about 0.13 barn (b); this is a factor of about 4400 times less
than the
235
U thermal fission cross-section, which is about 584 b. Irradiation of natural Mo targets in an epithermal
neutron flux of >1 10
13
n/cm
2
-s would produce higher specific activity
99
Mo because the epithermal neutron
cross-section for the
98
Mo neutron capture (n, ) reaction is about 6.7 b. This is a factor of about 50 times greater
13
than the thermal neutron capture cross-section but still well below the
235
U fission cross-section. However, a
marked increase in production rate is not seen due to the reduction in the thermal neutron flux available for
98
Mo
when other natural Mo nuclides are present. These have much higher thermal cross-sections (0.34 b, 13.4 b, 0.5 b,
14.4 b and respectively for
94, 95, 96
and
97
Mo) and hence capture neutrons that would otherwise be available for
98
Mo.
Most of these have much higher epithermal cross-sections as well.
Although the enriched
98
Mo would have four times the
98
Mo atoms compared to the natural Mo, much higher
production rates are often observed due to the (a) high epithermal neutron captures as well as (b) availability of the
neutrons otherwise lost to the competing reactions from other Mo isotopes. The actual increase seen will depend
upon the epithermal neutron flux available.
For the purpose of relative comparison, the specific activity of
99
Mo produced using the neutron capture (n, )
versus fission product (n, f) method is presented below:
(1) Neutron capture (n, ) production
High thermal neutron flux irradiation (EOB):
Natural isotopic abundance target ~1 Ci (37 GBq)
99
Mo/g of Mo irradiated
Highly enriched
98
Mo target 4 Ci (148 GBq)
99
Mo/g of Mo irradiated
(2) Fission product (n, f) production (EOB):
Reactor irradiation >10,000 Ci (370,00 GBq)
99
Mo/g of total Mo
However, scientists at the Delft University of Technology in the Netherlands developed a methodology to
increase the specific activity of neutron activated
99
Mo by a factor of more than 1000 by chemical separation of
99
Mo from the Mo target using SzilardChalmers chemistry, rendering a specific activity level in the order of that
produced via fission
99
Mo [3234]. The methodology can be applied to both natural and
98
Mo enriched targets.

This
process is currently in the stage of being scaled up towards demonstration of commercial production feasibility. The
target material is to be recycled.
Two types of natural Mo target material are typically used to produce (n, )
99
Mo: molybdenum trioxide and
molybdenum metal. These target materials are shown in Fig. 7.
FIG. 7. Natural abundance and high purity pressed sintered metal Mo targets (32 g) once irradiated at MURR shown with
molybdenum trioxide powder for comparison.
14
The crystalline density of molybdenum trioxide (MoO
3
) is about 4.7 g/cm
3
; the loose packed powder density
would be about half that. MoO
3
powder can be easily dissolved in sodium hydroxide (NaOH). The density of
pressed sintered metal targets is 30%95% of the theoretical density of 10.3 g/cm
3
(i.e. about 3.1 g/cm
3
to
9.8 g/cm
3
). Granulated Mo metal can also be used as a target material.
High density pressed sintered natural Mo metal targets are commercially available. They are typically
manufactured in the range of about 70%95% of theoretical density. Molybdenum metal targets can be dissolved in
alkaline hydrogen peroxide (H
2
O
2
) or electrochemically.
The metal form takes more time to dissolve than the powder form. However, the advantage of using metal is
that more natural Mo can be irradiated per target, producing a greater yield of
99
Mo per unit volume of irradiation
space and making more effective use of irradiation space.
The purity of the natural Mo target material should be >95% and should contain no detectable tungsten (W).
The irradiation of tungsten produces
188
Re (rhenium) by the radioactive decay of
188
W, which is difficult to separate
from
99m
Tc because it has similar chemical properties.
4.3.1.2. Enriched molybdenum-98
The use of
98
Mo target material (powder or metal) with an enrichment of >95% offers the advantage of
increased
99
Mo production yield. The purity of the enriched
98
Mo target material should be >95% with no detectable
tungsten (W) for the reasons described previously. However, because of the relatively high cost of highly enriched
target material, it might be necessary to recover the unused irradiated
98
Mo in a purified chemical form suitable for
new target production. This material is radioactive and must decay for at least 30 days before it can be classified as
non-radioactive.
4.3.2. Waste
Since neutron activation does not involve the presence of mixed fission products, the dose considerations for
production and waste handling and storage are significantly less. Shielding requirements through the whole process
are much less than for fission product
99
Mo. The other activation products present in the waste streams decay within
a reasonable period of time such that both solid and liquid wastes can be removed from the cell environment as low
activity waste after about 6 months.
Neutron activation based production involves no fissile material. Nuclear regulatory/safety approvals are
anticipated to be of similar complexity as the irradiation of other, non-fissile material.
5. ACCELERATOR BASED PRODUCTION
5.1. FISSION BASED (n, f) PRODUCTION USING ACCELERATORS
The use of accelerators as opposed to reactors to generate high fluxes of thermal neutrons (neutrons of
energy ~0.02 eV) for stimulating
235
U fission has been proposed for a number of years, initially using HEU. More
recently, yield calculations have been performed for LEU targets.
Two accelerator based production schemes are described in this report: The first uses a proton accelerator to
produce neutrons through the (p, n) reaction. The second uses a deuteron accelerator to produce neutrons through
the (D, n) reaction. These production schemes are illustrated in Fig. 2 [35].
15
5.1.1. Proton accelerator production
The driver for producing high energy protons has generally been a linear accelerator with high power, with the
combination of proton energy and beam current usually in the range of 150500 MeV with up to 2 milliamps of
beam current (~10
16
particles/s). The goal is to produce an order of magnitude more secondary neutrons inside the
target from
235
U fission.
As an example, the schematic system shown in Fig. 8 [35] consists of a target made of 0.5 mm thick metallic
LEU foils with a radius of 5 cm separated by 1 mm thick water channels for cooling. A target assembly containing
142 foils would generate nearly 5000 6 day Ci/week (185 000 6 day GBq/week) using a proton beam of 350 MeV
with a flux of 1 mA. In other words, this scheme would be suitable for large scale
99
Mo production.
5.1.1.1. Targets
The target(s) for this approach will consist of a series of LEU discs surrounded by a beryllium reflector to
enhance neutron interaction with the target material as well as a water moderator for thermalizing the neutrons.
5.1.1.2. Waste
The waste issues associated with accelerator based fission processes are essentially the same as for reactor
based fission processes. Both processes would produce liquid waste containing uranium fission products. However,
current reactor based processes utilize uraniumaluminium dispersion targets, which have a greater mass than the
uranium foil targets that would be used in the accelerator based process. Consequently, the accelerator based
process might produce smaller volumes of waste than current reactor based processes. Specific waste stream
volumes would not be known until the target configuration and design have been developed.
5.1.1.3. Regulatory issues
The fission based accelerator production methods are closest to the present gold standard of reactor based
thermal neutron fission of HEU; thus, the chemical processing would be identical. However, chemical processing
might have to be modified to account for the final target configuration discussed above. The LEU based production
process and products will have to be validated and approved by regulatory bodies.
FIG. 8. Subcritical reactor schematic using LEU target assembly with moderator and beryllium reflector [35].
16
5.1.2. Deuteron accelerators
Low energy accelerators can be used to produce neutrons via the D,T reaction or the photon induced breakup
of D
2
O. These neutrons can be directed to a target composed of a solution of uranyl nitrate or sulphate similar to the
solution reactor.
A high intensity neutron source with a very high neutron yield and efficiency has been developed at Phoenix
Nuclear Laboratory (PNL) [36]. The source was created by directing a collimated deuterium ion beam into a tritium
gas target in an aluminium container. This process produces yields consistent with those predicted by theoretical
calculations. The neutrons are produced via the low energy (300 keV) acceleration of deuterons on a tritium target.
Based on current yield estimates, this scheme could be used for medium scale production of
99
Mo to meet
regional needs. A cluster of devices could achieve large scale production.
The final design will require beam currents in the order of 50 mA, which have been exceeded in reliable, high
intensity light ion injectors by groups at LANL and LBNL. The lifetime of the ion source also must be increased
from several hours to months. The next generation prototype neutron source will incorporate higher voltage,
advanced pumping and improved beam focusing resulting in higher neutron output.
5.1.2.1. Targets
The target material is almost identical to aqueous homogenous reactor fuel consisting of a few kg of
235
U.
There are plans to study separation methods on both uranyl sulphate and uranyl nitrate target solutions. Questions
remain regarding the number of times that the solution can be recycled and reused due to waste product buildup.
The chemical processing of the solution reactor will follow established fission product chemistry. After about
five days of operation, the solution will be run through a chromatographic column to recover Mo from other fuel
components. This will be followed by the stripping of a Mo product from the column and further purification steps.
5.1.2.2. Waste
The waste produced is that associated with fission of
235
U. One challenge with this unit as well as with
solution reactors is how to deal with off-gas releases during operation (see Section 4.1.2).
Since
99
Mo will be produced from fission of
235
U, there are expected to be minimal regulatory hurdles for the
use of
99m
Tc in radiopharmaceutical applications. The
99m
Tc product is expected to meet USP specifications and be
of high specific activity so that it can be used directly in existing commercial generator systems (no new generator
needed).
Over time, fission products will accumulate in the solution as discussed above. Changes to the solution will
have to be addressed to satisfy non-nuclear/pharmacopoeia regulatory requirements.
5.1.3. Subcritical liquid LEU target for accelerator driven production of fission
99
Mo
The Advanced Medical Isotope Corporation (AMIC) is developing a
99
Mo production technology whereby a
tank of heavy water (deuterium oxide, D
2
O) is bombarded by photons (gamma rays) with energies of at least
2.224 MeV. Neutrons in the nucleus of the deuterium atoms in the heavy water are ejected from the deuterium
nucleus. Such a process results in a field of neutrons generated inside the tank. By dissolving uranium salts
homogeneously in the heavy water, the target material (the uranium) is directly held within the neutron source (the
deuterium nuclei). The neutrons generated by the photon bombardment cause some of the uranium atoms to fission,
producing useful fission products and extra neutrons that provide a boost to the neutron flux in the system.
The resulting fission product
99
Mo can then be extracted from the system and used. The uranium target
material is returned to the tank and can be used many times over. This system can run efficiently on LEU.
17
5.1.3.1. Targets
The target material is almost identical to aqueous homogenous reactor fuel consisting of a few kg of
235
U.
There are plans to study separation methods on both uranyl sulphate and uranyl nitrate target solutions. Questions
remain regarding the number of times that the solution can be recycled and reused due to waste product buildup.
The chemical processing of the solution reactor will follow established fission product chemistry although in
a continuous extraction mode. The approach will require the development of column approaches in a
semicontinuous or batch mode.
5.1.3.2. Waste
The waste produced is that associated with fission of
235
U. One challenge with solution reactors is how to deal
with off-gas releases during operation (see Section 4.1.2).
Since
99
Mo will be produced from fission of
235
U, there are expected to be minimal regulatory hurdles for use
of
99m
Tc in radiopharmaceutical applications. The
99m
Tc product is expected to meet USP specifications and be of
high specific activity so that it can be used directly in existing commercial generator systems (no new generator
needed).
Over time, fission products will accumulate in the solution as discussed above. Changes to the solution will
have to be addressed to satisfy non-nuclear/pharmacopoeia regulatory requirements.
5.2. PHOTON BASED (, n) PRODUCTION USING ELECTRON ACCELERATORS
The photon based (, n) production scheme uses a high powered electron accelerator (see Fig. 9) to irradiate a
high Z converter target such as liquid mercury or water cooled tungsten. High energy photons (known as
bremsstrahlung radiation) are produced by the electron beam as it interacts and loses energy in the converter target.
The photons are then used to irradiate another target material placed just behind the convertor, in this case
100
Mo, to
produce
99
Mo via the reaction
100
Mo(, n)
99
Mo. Table 1 [38] illustrates the photonuclear cross-sections for the
FIG. 9. High power electron accelerator manufactured by Mevex, Stittsville, Ontario, Canada [37].
18
production of various particles such as neutrons, protons and alphas. A separate convertor is not necessarily
required; the conversion can also be the front section of the Mo targets.
Based on theoretical data, estimated production yields can be determined as shown in Table 2 [39]. The
quantity of
100
Mo required for the production levels shown in the table is based on the following assumptions, taken
from Ref. [39] and representing an example developed to look at a scenario where production would be geared to a
regional market and which is not necessarily optimized):
Target enrichment >98 %;
Target material is recycled;
Two targets irradiated daily to produce 180 Ci (6660 GBq) of
99
Mo per target;
Recycle time set by decay: 10 mCi (0.37 GBq) can be handled with modest shielding, which requires 40 days
for decay before reusing the Mo;
Need (2 15) [g/day] 40 [days] = 1200 g of Mo target material as basic stock;
Nine cycles per year: losses per cycle expected to be small: estimated at 4 %;
Need 430 g per year to replace
100
Mo losses.
Under these assumptions and with the anticipated yields shown in Table 2, this production scheme could be
used for medium scale production of
99
Mo for regional markets. Obviously, multiple units could produce
99
Mo on
larger scales.
TABLE 1. PHOTONUCLEAR CROSSSECTION FOR PARTICLE EMISSION [38]
+
100
Mo
Abundance (%)
Threshold Energies (MeV)
,n ,p ,t ,He-3 , ,2n ,np ,2p ,3n
9.63 8.29 11.15 15.53 18.17 3.17 14.22 18.02 19.48 22.86
Note: Abundance refers to the natural abundance of
100
Mo.
TABLE 2. PRODUCTION OF
99
Mo BY A 50 MeV ELECTRON BEAM
Target mass
(g of
100
Mo)
Ci/100 kW
(GBq/100 kW)
at saturation
Specific activity
(Ci
99
Mo/g of Mo)
(GBq
99
Mo/g of Mo)
Power deposited
in target (kW)
0.29 100
(3 700)
360
(13 320)
2.2
1.0 210
(7 770)
20
(740)
4.8
2.3 300
(11 100)
147
(5 439)
11.4
9.1 518
(19 116)
57
(2 109)
16.4
70.6 900
(33 300)
12.8
(474)
29.0
Note: The saturated yield of
99
Mo for
100
Mo targets of various sizes irradiated by a 100 Kw electron beam incident on a converter target
is shown [39]. The columns provide the total activity, the specific activity and the actual power that is deposited in the production target.
19
5.2.1. Target materials
Molybdenum-100 is used as the target material for this production scheme (see Fig. 2). Enrichments of at least
99% are preferable to minimize possible side reactions that result in the production of unwanted technetium and
molybdenum isotopes with long half-lives. These isotopes are problematic for waste disposal and result in
increased radiation doses in patients.
100
Mo is available from European (including Russian Federation) centrifuges
with enrichments >92%.
Solid targets usually consist of the target material and an optional support (substrate or target holder
assembly). The target material needs to be firmly attached to the substrate
4
to ensure mechanical stability and good
surface contact for heat removal, which is commonly achieved by water cooling of the support plate (helium gas
cooling can also be used).
The target material can be an element (metal) or a compound. Generally, metallic targets are preferable to
compounds because they are of higher density and have higher thermal conductivity (and can therefore be irradiated
at a higher beam power). Technetium has been produced from molybdenum metal (foils, fibres) as well as
molybdenum trioxide targets [4043]. Target fabrication methods are currently under investigation. The most likely
method would involve some type of sintering of molybdenum metal powder.
5.2.2. Recycling of target materials
Recycling of the
100
Mo target material is essential because of its high cost. After processing, the residual
100
Mo will be mixed with the
99
Mo that was not removed during chemical processing. This material will have to be
stored until the level of
99
Mo and other co-produced radioactive species decay sufficiently to allow for handling.
Additionally, the other co-produced isotopes such as
95
Nb can contaminate the
99
Mo produced in the next cycle. The
level of contamination is related to the level of other molybdenum isotopes present in the original enrichment of
100
Mo. For example,
95
Nb is predominately formed from the
98
Mo(p,o) reaction and thus the amount of
98
Mo in the
100
Mo target material will be reflected as a final contaminant in the recycled
100
Mo. The separation of molybdenum
and niobium is possible but such chemical separation steps can result in the loss of
100
Mo.
A process will need to be developed to recover the
100
Mo in a physical state suitable for new target preparation
(i.e., metal powder). This process will probably need to be carried out in a facility able to handle radioactive waste.
Similar processes are already in place for the production of other radionuclides used in nuclear medicine such as the
203
Tl(p,3n)
201
Pb
201
Tl reaction system.
5.2.3. Waste
The production cycle produces very little process waste. No fission product waste is present and because the
bulk of Mo target material is recovered for recycling into targets, there would be very little radioactive waste
generated from routine production. However, the flux of high energy neutrons generated during
99
Mo production
will activate surrounding components and facility walls.
The primary regulatory issue for this production method is associated with the generator system for the
delivery of the
99m
Tc: The specific activity of
99
Mo is too low for use in existing commercial generator systems that
use alumina columns. The existing columns are designed to capture multiple curies (gigabecquerels) of
99
Mo with
a specific activity of greater than 5000 Ci/g (185 000 GBq/g). The
99
Mo produced by the above method yields a
specific activity of less than 10 Ci/g (370 GBq/g). A number of alternative generator systems have been proposed,
but none is proven to routinely deliver
99m
Tc of specific purity and also allow recycling of
100
Mo. Thus, there are
health and safety related issues as well as nuclear safety issues that must be addressed. These issues include the
impact on the quality of the
99m
Tc as produced by this method (breakthrough of the
99
Mo from a different generator
4
This may be generally true but is not true for the NorthStar target material. The sintered metal disks need no support; they are
loosely held in a frame to keep the spacing between the thin disks constant to allow cooling by a stream of pressurized He gas.
20
system) and the challenges of moving significant quantities of
100
Mo contaminated with
99
Mo from the site of use
back to the production site. Any new generator would be considered as a new drug that would need approval from
regulators (i.e. a market authorization or new drug application).
5.3. NEUTRON INDUCED PROCESS
100
Mo(n,2n)
99
Mo [44]
This process is a variation of the process discussed above in that the target and product will be essentially the
same. The neutrons used for the production of
99
Mo are derived by the D(T,n) reaction yielding neutrons of 14 MeV.
The proposed (n,2n) reaction has a cross-section of approximately 1.5 b in this energy range. The major challenge
for this approach will be in producing sufficient flux of neutrons to be viable.
Please refer to the discussion in Section 5.2.1 of this report.
5.3.2. Recycling of target materials
Recycling of the
100
Mo target material is essential because of its high cost. After processing, the residual
100
Mo will be mixed with the
99
Mo that was not removed during chemical processing. This material will have to be
stored until the level of
99
Mo and other co-produced radioactive species decay sufficiently to allow for handling.
A process will need to be developed to recover the
100
Mo in a physical state suitable for new target preparation
(i.e. metal powder). This process will probably need to be carried out in a facility able to handle radioactive wastes.
5.3.3. Waste
5.4. DIRECT PRODUCTION OF
99m
Tc USING PROTON ACCELERATORS
Beaver and Hupf first reported the feasibility of producing
99m
Tc by proton irradiation of
100
Mo via the (p,2n)
reaction (Fig. 2), with theoretical yields of 15 Ci/h (555 GBq/h) using 22 MeV protons at 455 A [45]. More
recently, Scholten and colleagues demonstrated that a peak cross-section of 200 mb achieved at approximately
17 MeV, with a peak production of 102.8 mCi/A (3.80 GBq/A) at saturation. They suggested that the use of a
>17 MeV cyclotron could be considered for regional production of
99m
Tc [46]. Takacs et al. found a peak
cross-section of 211 33 mb at 15.7 MeV [47]. Higher energy cyclotrons can produce a higher total yield of
99m
Tc because the protons can more deeply penetrate the targets [48, 49].
The direct production of
99m
Tc from proton irradiation of
100
Mo via the (p, 2n) reaction (Fig. 2) has also been
performed using natural and enriched
100
Mo metal foils. Using
100
Mo at an enrichment of 97.46% (
100
Mo is now
available at greater than 99.5% enrichment), Lagunas-Solar obtained greater than 99.99% radionuclidic purity at
the end of processing in his experiments [48]. According to these authors, however, robust systems have not been
reported in the literature for plating and recovering
100
Mo from a solid support to create reusable targets at low cost
while maximizing
100
Mo recovery.
99
Mo is co-produced directly during the production of
99m
Tc via the
100
Mo(p,pn) reaction. However, such
production requires higher energy cyclotrons and offers much lower yields than direct
99m
Tc production [46, 48].
The yield and expected radionuclidic impurities of proton reactions on selected isotopes of Mo have recently
been presented along with the measured quantities of
99m/g
Tc co-produced. As an example, Table 3 lists sample
21
isotopic compositions of
100
Mo that are commercially available. The supply and cost of enriched
100
Mo would need
to be evaluated to determine the commercial feasibility of this production system.
5.4.1.1. Electro-deposition/aqueous aolution
Electroplating of metals from aqueous solutions is a standard industrial process. There are unique
characteristics associated with metallic coatings for use as targets for cyclotron bombardment that must be taken
into account (see for example the IAEAs report on Standardized High Current Solid Targets for Cyclotron
Production of Diagnostic and Therapeutic Radionuclides (Technical Report Series No. 432)) .It is often the method
of choice for target preparation because many metals can be deposited on target substrates as well adhering,
uniform layers. Refractory metals such as molybdenum cannot easily be deposited from aqueous solutions due to
their high affinity for oxygen [50]. However, Fink describes the electroplating of tungsten, thorium, aluminium and
molybdenum from particular alkaline solutions [51]. His publication focuses mainly on tungsten plating, but the
process could be applied for molybdenum as well. A similar method is described in Ref. [52]. Typically this
approach results in a mixture of Mo metal and Mo oxide.
5.4.1.2. Non-aqueous solution
Ionic liquids have been developed as solvents for the electroplating of metals that cannot be deposited from
aqueous media. Ionic liquids are purely ionic, salt-like materials, which are by definition liquid below 100C. They
typically consist of organic cations, such as imidazolium, pyridinium, or pyrrolidinium, and an organic or inorganic
anion (e.g. tosylate, alkyl sulphate, tetrafluoroborate). Ionic liquids are thermally and electrochemically stable.
About 300 ionic liquids are commercially available. While thick coats can be achieved, the high temperatures and
water sensitive molybdenum salts require significantly more complex and specialized equipment [53, 54].
Recently, a description of a successful means for electroplating Mo metal has been published [55]. However
the thickness of this plate is generally not sufficient to be used in the preparation of thick targets.
5.4.1.3. Metal foils
100
Mo is currently available in foil form up to enrichments of >97% to 99%. For high current targets (500 A),
the estimated amount of molybdenum needed is 1g; lower current targets can probably be designed with as little as
100 mg of foil with proper backing material. Unused foils could be sent back after decay for recycling and
repurification, preferably to a central processing facility for scaling economy.
5.4.2.
99m
Tc pertechnetate yields and purity
The major radioisotope produced as a contaminant for the
100
Mo(p,2n) reaction is
99g
Tc. As shown in Table 3,
the only other significant Mo isotope present in the target material is
98
Mo, which can lead to the production of
98
Tc
TABLE 3. TYPICAL CERTIFICATES OF ANALYSIS FOR >97%
100
Mo
a,b
Isotope 92 94 95 96 97 98 100
% 0.005 0.005 0.005 0.005 0.01 2.58 97.39
% 0.06 0.03 0.04 0.05 0.08 0.47 99.27
a
For example, as found on the web sites of Trace Sciences (http://www.tracesciences.com/) and Isoflex
(http://www.isoflex.com/).
b
It should be noted that the enrichment of
100
Mo determines the relative yield, while the percentage abundances of the lighter
molybdenum isotopes reflects the isotopic purity of the
99m
Tc.
22
and
97
Tc through (p,n) and (p,2n) reactions [48, 56]. Although both of these radioisotopes are long lived (2.6 and
4.2 million year half-lives, respectively), they contribute little to the activity in a
99m
Tc batch (and therefore little to
patient dose) or the total mass of the Tc (thus lowering its specific activity) because their production rate is orders
of magnitude lower than that for
99m
Tc.
Using 99.5% enriched
100
Mo produces very pure
99m
Tc. The major contaminants include
99g
Tc and
99
Mo.
Trace amounts of
95
Nb are produced from the
98
Mo(p,o) reaction, the amount being dependent upon the amount of
98
Mo present in the target material. With a 19 MeV proton beam irradiating for 6 hours at 200 A the
99m
Tc
produced represents 99.6% of the total technetium radioactivity at end-of-bombardment (with the proviso that all of
the long lived species such as
97, 98, 99g
Tc are considered stable) [57]. The major radioactive contaminants are
96
Tc
and
95
Tc, each accounting for less than 2 mCi (0.07 GBq).
In terms of trace metal contaminants, the major concern will be with respect to metal ions that could interfere
with Tc labelling of radiopharmaceuticals. The metals present in the target material that act as contaminants include
baluminium, iron and tungsten, all of which are trace elements in the Mo target material. The quantities of
impurities are in the order of ppm as indicated on the certificate of analysis
5
from the vendor.
As a means of determining the amount of
99g
Tc produced by direct production from the
100
Mo(p,2n) reaction,
it has been measured directly by liquid scintillation which will be cross calibrated via ICP-MS. Results are shown
in Fig. 10 [58] and Table 4.
Table 5 shows calculated
99m
Tc yields for various proton energies, beam currents and irradiation times. Based
on the half-life of
99m
Tc and the predicted yields for production at various energies, the direct production route is
viewed as small scale.
5
A certificate of analysis is a factsheet from the supplier indicating the chemical content of all materials present as determined
by chemical analysis. It is considered an official document of purity.
FIG. 10. Experimental excitation function for the
100
Mo(p,2n)
99g
Tc and
100
Mo(p,2n)
99m
Tc reactions. The Short designation refers to
irradiations of 1 A for 600 seconds while the Long indicates irradiations lasting 10 hours at 20 A. The
100
Mo had an enrichment
of 97.5% while natural Mo was of natural composition enrichment of
100
Mo=9.63%. [58].
23
5.4.3. Waste
This production scheme produces very little waste when the bulk of Mo target material is recovered for
recycling. As with any accelerator production facility there will be activation of beam line components and target
holders. While the concrete shielding walls will become radioactive, this can be minimized by using low sodium
content concrete which is standard for constructing such facilities. The above bulk waste is generally low level
while the components directly hit by the proton beam will be high level but generally small in volume.
TABLE 4. EXPECTED MASS RATIO OF THE META-STABLE TO GROUND STATE OF
99m
Tc UNDER
DIFFERENT IRRADIATION CONDITIONS
Energy
(loss in target)
MeV
Ein Eout
1 hour irradiation 3 hour irradiation 6 hour irradiation
Ratio
(%)
99mTc
yield
(MBq/A)
Ratio
(%)
99mTc
yield
(MBq/A)
Ratio
(%)
99mTc
yield
(MBq/A)
18 10 28 543 25 1458 21 2490
20 10 26 661 24 1774 20 3029
22 10 25 747 23 2006 19 3425
24 10 24 804 22 2158 19 3685
TABLE 5. ESTIMATED PRODUCTION YIELDS FOR
99m
Tc BASED ON MEASURED CROSSSECTION
DATA [58].
Cyclotron Energy (MeV) Current (mA) Irradiation time (h) Theoretical activity at EOB (Ci)
CP42
18 0.2 3 7.6
18 0.2 6 13
18 0.2 12 19.5
22 0.2 3 9.8
22 0.2 6 16.7
22 0.2 12 25.0
TR19
18 0.2 3 7.6
18 0.2 6 13
18 0.2 12 19.5
18 0.5 3 19.1
18 0.5 6 32.5
18 0.5 12 48.8
GE PET trace
16.5 0.08 3 2.4
16.5 0.08 6 4.2
16.5 0.08 12 6.3
16.5 0.16 3 4.9
16.5 0.16 6 8.4
16.5 0.16 12 12.5
Note: Thick target yields are for the proton energy range from beam on target down to 10 MEV where the excitation function is too
low to provide any additional product. The energy bite defines the stopping power (areal density) of the target material.
24
In the direct production and distribution of
99m
Tc, a new product or process that will need approval from the health
agencies (market authorization) and each manufacturing site should be GMP compliant (similar to PET cyclotron
centres for commercial distribution). Labelling the efficiency of each cold kit with the new
99m
Tc solution will require
validation, at least internal validation from the technetium supplier or external validation with health agencies.
The use of recycled
100
Mo should also be validated and the purity level of the
99m
Tc produced with the
recycled Mo target checked with quality procedures.
6.
99
Mo/
99m
Tc GENERATOR SYSTEMS AND CHEMISTRY
6.1. HIGH SPECIFIC ACTIVITY (FISSION PRODUCT) GENERATORS
6.1.1. Principles of generator operation
A
99
Mo/
99m
Tc generator, or technetium generator, is a device used to recover and concentrate technetium from
99
Mo. A conventional generator consists of an alumina (Al
2
O
3
) column about the size of a short pencil; associated
tubing, valves and filters for extracting technetium; and lead shielding for radiation protection (see Fig. 11.)
The column is loaded with
99
Mo at the generator manufacturing facility before shipment to a hospital,
radiopharmacy or clinic. The
99
Mo in the column decays to technetium with about a 66 hour half-life. About 88.6%
of the
99
Mo decays to
99m
Tc; the remainder decays directly to
99
Tc. Technetium is extracted (eluted) by passing a
saline solution through the column.
The half-life of
99
Mo is about 10 times longer than that of
99m
Tc. Approximately 50% of the steady state
activity is reached within one
99m
Tc half-life and approximately 75% within two half-lives. Therefore,
99m
Tc can be
FIG. 11. External and cutaway view of LMIs TechneLite

99
Mo/
99m
Tc generator. Photos used with permission from Lantheus Medical
Imaging, Inc. All rights reserved.
25
eluted from the generator to obtain patient dose quantities as often as every 6 hours. The useful life of a generator is
between three and five times the half-life of
99
Mo (i.e. 814 days). As a consequence, generator users typically
purchase at least one generator per week, or order several on a staggered basis throughout the week.
The elution efficiency is an important factor when evaluating the performance of various sorbent materials in
99
Mo/
99m
Tc generator systems. All practical generator designs exhibit good elution efficiency. Additionally, all
99m
Tc generator systems, regardless of type, must be manufactured to the requirements of an established GMP
programme.
6.1.2. Chemistry of alumina column based generator and technetium cows
Most commercial
99
Mo/
99m
Tc generators use column chromatography, in which
99
Mo in the form of
molybdate (MoO
4
2
) is adsorbed onto acidified alumina (Al
2
O
3
). A typical column contains 23 g of alumina
(Fig. 11). When the
99
Mo decays it forms pertechnetate (TcO
4
), which because of its single charge is less tightly

bound to the alumina. Passing a normal (0.9%) saline solution through the column elutes sodium pertechnetate. The
sodium pertechnetate can then be added in an appropriate concentration to the organ specific pharmaceutical or can
be used directly for specific procedures.
The two most important factors for the design of an alumina column based
99m
Tc recovery system are high
elution efficiency (typically 85%) and minimal Mo breakthrough. Fission product based technetium generators
manufactured in the USA are commercially available in activity ranges of 118 Ci (37666 GBq) at the
manufacturers stated time of calibration
6
.
Uzbekistan currently uses enriched
98
Mo oxide targets to produce (n, )
99
Mo for use in standard size alumina
column generators. POLATOM is supplying the materials necessary for Uzbekistan to manufacture their own line
of low specific activity alumina column
99
Mo/
99m
Tc generators. A typical alumina column supplied by POLATOM
to Uzbekistan is shown in Fig. 12.
IPEN routinely manufacturers about 320 alumina column generators weekly to meet Brazils domestic need.
The activity of the generators range from 250 mCi to 2 Ci (9.2574 GBq). The fission product
99
Mo used in these
generators is imported from Argentina, Canada and South Africa [59]. The sodium molybdate supplied to IPEN by
both Argentina and South Africa is produced from LEU. A typical
99
Mo/
99m
Tc generator manufactured by IPEN is
shown in Fig. 13.
CNEA LEU based
99
Mo production satisfies the Argentine national demand, which is approximately 200 Ci
(7400 GBq) (calibrated to 3 days).
99
Mo/
99m
Tc generators are manufactured by two private Argentine companies.
The size of the generators range from 500 mCi to 2 Ci (18.574 GBq). CNEA exports LEU based
99
Mo to Latin
America, including neighbouring Brazil.
6
Designated on the paperwork by the manufacturer.
FIG. 12. Typical alumina column manufactured by POLATOM.
26
6.2. LOW SPECIFIC ACTIVITY
99
Mo/
99m
Tc RECOVERY METHODS
6.2.1. Chemistry
As a point of reference, the production of
99
Mo from thermal neutron induced fission of
235
U typically
generates material with a specific activity greater than 5000 Ci/g (>185,000 GBq/g). This level of specific activity
permits the extraction of the
99m
Tc daughter nuclide using adsorption chromatography, which exploits the relative
immobility of the MoO
4
2
anion relative to the TcO
4
anion on alumina. Modern Tc generators contain alumina

columns loaded with
99
Mo. These columns are washed (eluted) with saline solutions to obtain
99m
Tc.
Production of
99
Mo from photonuclear or proton reactions on enriched Mo targets produces material with a
lower specific activity. Extraction of
99m
Tc from this material requires larger volumes of alumina to accommodate
the non-activated molybdenum. This results in high elution volumes and ultimately low Tc concentrations, too low
for radiopharmaceutical production [6064].
Alternative methods for the extraction of
99m
Tc from enriched molybdenum target material have been reported
and reviewed [45, 65]. These methods fall into three general categories: (a) adsorption chromatography
(as discussed above but with Mo being incorporated into the support material rather than being adsorbed on it
(zirconium or titanium molybdate gels) or columns where Tc is sorbed on the column material and Mo passes
through unadsorbed, (b) liquidliquid extraction and (c) sublimation.
Tc isolation via sublimation, or thermochromatographic separation, involves heating irradiated Mo followed
by recovery of the technetium activity from various adsorption zones within the cooling apparatus. NaTcO
4
is
isolated by rinsing the apparatus with a hot 0.1 mM NaOH solution followed by purification on alumina.
Conventional heating of a MoO
3
target was reported to yield ~70% of the Tc in the sample in approximately
20 min [66, 67], which is not quite as efficient as adsorption based generators which typically yield
99m
Tc at 85%
efficiency. The radiochemical purity of Tc isolated using sublimation is typically >99% and Mo breakthrough is
below detectable limits [65]. Bigott et al. reported an improved method that combines purification and
concentration into one step, thereby decreasing the amount of time needed to complete the process [67].
FIG. 13.
99
Mo/
99m
Tc generator manufactured by IPEN.
27
6.2.2. Liquidliquid generator concept
Liquidliquid extraction begins with the dissolution of solid molybdenum target material in an acidic medium
(HCl, H
2
O
2
mixture), which transforms Mo into a cationic species (MoO
2
2+
) and Tc into TcO
4
by the addition of
ammonia. Ammonium pertechnetate can be extracted from the aqueous solution of ammonium molybdate by
methyl ethyl ketone (MEK) as ammonium pertechnetate [43, 68]. Once the MEK is evaporated, the ammonium
pertechnetate can be dissolved in saline solution.
MoO
3
targets, on the other hand, necessitate the use of a different method. MoO
3
is dissolved in ammonia and
dissolved in 30% H
2
O
2
. The Tc is then extracted into MEK as discussed in the previous paragraph. Radiochemical
yields of 60% have been reported with overall isolation times of approximately 1 hour [42, 69].
In either case, sodium hydroxide can be used instead of ammonia to increase the pH of the solution. Below is
a more detailed description of a specific MEK generator system.
A standard approach to separating ions is through liquidliquid extraction where there is a polar and
non-polar solvent and the ions to be separated have a different affinity for the two solvents. The degree of
separation is directly related to the solubility of the different ionic species in the respective solvents. For separating
molybdenum and technetium ions a mixture of methyl ethyl ketone 1% aqueous hydrogen peroxide added to the
NaOH/
99
Mo solution is used.
The Mo is dissolved in 5.0 N NaOH and transferred via vacuum to an extraction reservoir (ER). Sufficient
5.0 N NaOH solution is used to wash the transfer vessel and lines and fill the ER to the extraction volume. The
extraction volume is specific for each unit and is determined by the placement of the extraction tube located
approximately midway in the ER.
The extraction cycle consists of adding a mixture of methyl ethyl ketone 1% aqueous hydrogen peroxide to
the NaOH/
99
Mo solution and mechanically stirring the ER contents to selectively remove the
99m
Tc from the
aqueous layer into the organic layer. Hydrogen peroxide is added to keep the
99
Mo and
99m
Tc in the appropriate
oxidation state. After the suspension is allowed to separate, the upper MEK layer is removed by vacuum draw and
transferred to a 20 mL syringe filled with acidic alumina (~15 mL). The MEK
99m
Tc solution is passed through the
alumina column to remove any
99
Mo that may be transferred with the MEK solution. Since the hydrogen peroxide
is added as an aqueous solution, there is a small increase in the aqueous volume after each MEK addition. However,
this small aqueous volume that is removed with each MEK extraction thus inadvertently removes a small amount of
99
Mo that is trapped by the alumina column and lowers the overall amount of
99
Mo for future extractions.
The MEK
99m
Tc solution eluted through the alumina column is transferred to a stainless steel evaporation
vessel (EV). The EV is heated to ~70 C and subjected to a slight vacuum to hasten evaporation of the MEK. After
the MEK has been removed, sterile saline is added to the EV to dissolve the
99m
Tc. The sterile saline is then
transferred through a sterilizing filter into a sterile vial for further processing into radiopharmaceuticals after
appropriate QC (e.g. Mo, hydrogen peroxide, alumina and MEK breakthrough, pH). Several alternatives for
liquidliquid extraction of pertechnetate have also been reported [7072].
6.2.3. Low cost/high efficiency wet extraction using an automated unit
An example of the adsorption column approach where technetium is adsorbed and Mo is not is detailed below.
Recently, Chattopadhyay and co-workers reported a method to extract
99m
Tc from (n,) activated
98
Mo [73]. Using
inexpensive and commercially available strong base anion exchange Dowex 1 8 resin (25 mg, 1 mm 14 mm),
the authors report the ability to selectively trap and separate [
99m
Tc]TcO
4
from a low specific activity Mo solution

after transient equilibrium has been achieved. Na
99m
TcO
4
wasn recovered from the Dowex 1 8 column using
tetrabutylammonium bromide (TBAB) in CH
2
Cl
2
and purified by immobilization on a neutral alumina column.
This column was washed with water and Na
99m
TcO
4
was isolated by flushing with physiological saline. Subsequent
quality control revealed no significant levels of trace metal contaminants or organic components. Tc recovery yields
of greater than 90% were demonstrated and radiochemical purity was consistently over 99%.
As with the liquidliquid extraction, the Mo target containing Tc will be dissolved in 5M NaOH and passed
through the Dowex 1 8 resin. The resin will be washed with saline and the Tc recovered using 0.2 mg/mL solution
of TBAB. This eluate (containing the Mo) will be applied to a neutral alumina column, dried, flushed with water
and the [
99m
TcO
4
] will be eluted from the column using 35 mL of physiological saline. This process can be easily
automated.
28
6.2.4. Post-production isotopic separation [74, 75]
The use of a high throughput, high efficiency, rapid off-line isotope separators to extract
99
Mo

of high specific
activity that had been produced via
98
Mo(n,) and/or
100
Mo(,n) routes would allow for introduction of the
99
Mo

into
existing supply chains.
A high power ion source coupled to a high resolution dipole magnet would be used to generate beams of
molybdenum ions and separate the respective isotopes with the aim of producing
99
Mo

with a specific activity of
greater than 1000 Ci/g (37 000 GBq/g). The feedstock for the separator system will be low specific activity
99
Mo
generated from the thermal neutron capture of
98
Mo or the photon induced neutron emission of
100
Mo. This
approach does not require HEU or LEU targets and could generate commercial quantities of
99
Mo

suitable for use
in existing commercial technetium generators.
Preliminary proof of principle experiments have demonstrated the capability for generating intense Mo ion
beams. A test stand incorporating all of the elements of the separator system is underway with the expectation that
a beam current and ionization efficiency can be achieved that will make it possible to use this device for producing
commercial quality and quantities of
99
Mo. This test stand is shown in Fig. 14.
This separation system has several advantages: the
99
Mo

produced can be directly used in existing commercial
generators; there is no need for uranium targets and it can be used to generate the required target material
(
98
Mo/
100
Mo) during the separation process. In addition, the system can be used in conjunction with neutron or
photon sources to create a distributed delivery system.
Each separator is designed to handle approximately 100 6 day curies (gigabecquerels) per week. A cluster of
separators would be required to obtain regional supply and would be classified as a medium scale production
capability.
FIG. 14. Ion source test stand showing ion source in the Faraday cage on the left, the beam line with analysing elements, the blue
analysing magnet and the collection Faraday cup on the far right. (Courtesy of Ruth, T., TRIUMF/AAPS).
29
6.2.4.1. Waste management
The waste associated with electromagnetic separators will depend on the efficiency of the ion source. The
waste will be composed of whatever
99
Mo

does not get injected into the separator. There will inevitably be losses of
99
Mo

in the separator system and in the collection process itself. Nevertheless, the only radioactive contaminants
associated with this process are
99
Mo

and the
99g
Tc that grows in from the decay of
99
Mo,

either in storage or in situ
with the separator.
As with any accelerator production facility there will be activation of beam line components and target
holders. While the concrete shielding walls will become radioactive, this can be minimized by using low sodium
content concrete which is standard in constructing such facilities. The above bulk waste is generally low level while
the components directly hit by the proton beam will be high level but generally small in volume.
The goal of this approach is to prepare
99
Mo

with chemical, radionuclide and specific activity specifications
that are equivalent to
235
U fission. There should be no significant challenges to regulatory approval if such
specifications can be achieved.
6.2.4.3. Stable isotopes
The phototransformation and direct production routes require high purity enriched
100
Mo as target materials.
The proponents of the separator project have proposed using their device for the production of
100
Mo (and
98
Mo).
6.2.5. Solvent extraction
Solvent extraction technology is the most common method for separating
99m
Tc from low specific activity
99
Mo. Generators based on MEK extraction of TcO
4
from alkaline aqueous molybdate solutions have been widely

used for the production of
99m
Tc [76]. The solvent extraction method can produce, under well controlled conditions,
99m
Tc of high purity comparable to that obtained from a high specific activity alumina column generator. This
extraction method is used routinely in India, Peru and the Russian Federation.
99m
Tc can be eluted from a zirconium/titanium molybdate gel type generator column (so called solid solvent
extraction) using a volatile solvent such as acetone. As reported in Ref. [77], a
99m
Tc elution yield of 80% has been
achieved by acetone extraction of
99m
Tc from a titanium molybdate gel column, followed by evaporation of acetone
and recovery of the pertechnetate with saline. India routinely produces a limited number of gel generators and
supplies. Kazakhstan also produces gel generators.
6.2.6. Sublimation extraction
A process has also been developed to extract and recover
99m
Tc through sublimation using a sublimation
process. An irradiated Mo oxide target or Mo metal target (the latter after dissolution and calcining to MoO
3
) is
heated in a furnace in a stream of oxygen between 600C and 750C. The Tc sublimes to Tc
2
O
7
[78 80]. NorthStar
Medical Radioisotopes, LLC has an exclusive licence from INL for this technetium recovery technology.
Additional information about this technology is provided in section 3.6 and annex IV of Ref. [96].
6.2.7. Post-elution concentrator
Some of the processes described above produce lower than required concentrations of
99m
Tc. In principle,
there is no impediment to in-line concentration of low activity concentration
99m
Tc solutions using simple post-
elution concentration technologies. Methods for effective concentration of saline generator eluents have in fact
been widely used in clinical practice to obtain
188
Re from the
188
W/
188
Re generator system [81, 82]. The specific
activity of reactor produced
188
W is low (<810 Ci (296370 GBq)
188
W/g
186
W target material) and requires large
(high mass) generators.
30
In a
188
W/
188
Re generator system, a normal saline eluent is first passed through a small silver nitrate
impregnated column which traps the chloride anion converting the solution to a nitrate media and allowing
perrhenate to be loaded onto a second (anion exchange column). The perrhenate can be subsequently stripped from
this column with a small volume of normal saline, making it ready for kit radiolabelling. The concentration factors
in this technique can be as high as 1020. Many generator prototypes using this concept of post-elution dual column
purification/concentration have been reported [83].
Another dual column purification/concentration process was developed recently to separate
99m
Tc from the
low specific activity
99
Mo based on pertechnetate ion selective columns. A special generator system based on this
process has been developed (see Fig. 15). An alkaline Mo solution is fed into a column specifically designed to
adsorb pertechnetate. Once the column is loaded, it is washed to remove any absorbed molybdate. Following the
wash, technetium is stripped from the column with normal saline solution, which is passed through an alumina
guard column to remove any impurities (primarily Mo). The eluate is then passed through dual 0.22 m sterility
filters [30, 31].
A single column process for purification/concentration of dilute solutions of
99m
Tc was developed a long time
ago [84] but has been improved recently by automated operation [85]. This process is based on the selective
adsorption of
99m
Tc eluted from a
99
Mo column onto a significantly smaller sorbent column. In the following step
the technetium is stripped from the column with a small volume of saline solution suitable for injection. Optionally,
the sorbent column can be washed prior to stripping. The automated purification/concentration unit coupled
radionuclide generator shown in Fig. 16 is a versatile system which can be used for the production, for example, of
99m
Tc,
188
Re,
90
Y and
68
Ga, producing solutions of high radioactive concentration.
6.3. LOW SPECIFIC ACTIVITY GENERATOR TYPES
6.3.1. Technetium selective separation system
A new generator system based on technetium selective separation (aqueous biphasic extraction
chromatographic, or ABEC) has been developed [86, 87] that can be used with low specific activity
99
Mo (Fig. 15).
The technetium is eluted from the ABEC column using normal saline and is passed through an alumina guard
column. The volume activity of
99m
Tc produced by this system is comparable to that of an alumina column
generator loaded with fission product (i.e. high specific activity)
99
Mo. This new generator system is currently in
FIG. 15. Newly developed automated chemical separation unit (TechneGen) from NorthStar Medical Radioisotopes, LLC.
31
the process of being validated for nuclear pharmacy use through a new drug application on file with the US Food
and Drug Administration.
A commercial system based on technetium selective separation is the commercially available Automated
Radionuclide Separator (ARSII) chemical separation unit [8890]. This system was developed by NorthStar
Medical Radioisotopes and is the predecessor system to the TechneGen device shown in Fig. 15. The ARSII unit
(Fig. 16) is being used in a clinical trial involving other radioisotopes [91, 92].
6.3.2. Jumbo alumina column generator
Researchers at BRIT have developed a means for using low specific activity
99
Mo (0.20.4 Ci/g or
7.515 GBq/g)
99
Mo in a large (jumbo) alumina column generator. They have developed a simple procedure for the
concentration of
99m
Tc eluates using a small Dowex 1 column for trapping [
99m
TcO
4
]
. The primary column contains

60 g of alumina [84].
6.3.3. Gel moly generator
The concept for the
99m
Tc chromatographic gel generator was developed by Evans et al. [93] in the mid-1980s.
The technical maturity of this gel based system has advanced significantly since then. Recent advances in
radiopharmaceutical diagnostic applications (e.g.
99m
Tc sestamibi for myocardial perfusion studies) require
pertechnetate of moderate to high
99m
Tc activity concentration. A gel moly generator, which is used exclusively
with low specific activity
99
Mo, can provide the necessary post-elution
99m
Tc activity concentration. Typically if a
gel generator is prepared using (n, )
99
Mo alone, its strength is ~270 mCi (10 GBq) /generator and upon elution
with 10 mL saline, it will give
99m
Tc at ~20 mCi/mL (0.74 GBq). Post-elution concentration can provide
99m
Tc at
~100140 mCi/mL (3.75.2 GBq/mL) (typically 57 times concentrated).
Loading low specific activity
99
Mo in a traditional alumina column technetium generator requires a large
alumina column. This is because the capacity of alumina to adsorb Mo is limited (~20 mg Mo/g of alumina). Large
eluent volumes are required to obtain patient dose quantities of
99m
Tc from these columns. These eluent volumes
contain unacceptably low concentrations of pertechnetate for most radiopharmaceutical diagnostic procedures. A
post-elution concentration column is required to increase the activity concentration.
In 1999, it was reported that low specific activity gel moly generators were used to satisfy more than 30% of
Chinas domestic
99m
Tc demand [16]. It has been demonstrated that
99m
Tc can be effectively eluted from a gel based
recovery system in exactly the same manner and with identical quality to that obtained from a fission based
technetium generator [94].
FIG. 16. Automated chemical separation unit (ARSII) developed by NorthStar Medical Radioisotopes.
32
A gel moly generator contains
99
Mo in the form of an insoluble zirconium or titanium molybdate hydrous gel
with a pH of 29.
The dried gel contains about 25% by weight of molybdenum and has the characteristics of a cation exchanger.
The passage of an aqueous eluent (typically either purified water or normal saline) through a column of molybdate
gel releases
99m
Tc. However, an additional mini-column of alumina is required to remove impurities (e.g.
99
Mo, Zr,
Ti) in the eluate. A typical gel moly generator is shown in Fig. 17.
An example of a gel generator for low specific activity
99
Mo is the technetium generator system shown in
Fig. 17, which can be used for the production of high specific activity solutions containing several radioisotopes
(e.g.
99m
Tc,
188
Re,
90
Y and
68
Ga) [85, 95]. In the system developed for Mo/Tc separation, this device is based on the
selective adsorption of
99m
Tc eluted from the
99
Mo column onto a significantly smaller sorbent column. In the
following step, the technetium is stripped from the smaller column with a small volume of injectable saline
solution. Optionally, this small sorbent column can be washed to remove any impurities that may have sorbed onto
the column. Following the wash, the
99m
Tc nuclide is stripped from the column with a small volume of solution
suitable for injection or for investigational purposes.
Elution of
99m
Tc from the generator followed by eluate purification/concentration is performed using a low
cost automated bench top system [85]. This system was designed based on the timing sequence of seven processing
steps without feedback control. The variable flow rate of eluents used for elution/purification also ensure the
FIG. 17. The Geltech
99m
Tc generator, manufactured by BRIT, is a dual column system comprised of a primary zirconium molybdate
99
Mo gel column and a secondary purification acidic alumina column.
33
optimization of operating times with respect to the different adsorption/desorption kinetics of daughter radionuclide
ion species, which is controlled by the sorbent and ion exchange resin used in the generator and the purification
columns.
The conditions under which the zirconium or titanium molybdate is prepared will modify the cavity sizes in
the gel, its diffusion properties and thus the generators performance. Factors such as pH, the molar ratios of
zirconium (or titanium) to molybdenum, solution concentrations, the order of reactive agent addition and the drying
temperature of the final product must be properly controlled to consistently reproduce the properties of the gel.
As is the case for an alumina column recovery system, the radiochemical purity of
99m
Tc eluted from a gel
moly generator can be impacted by radiolysis, changes in temperature or pH and the presence of reducing or
oxidizing agents. Finished product quality control testing clearly demonstrates that the radiochemical purity is
equivalent to that of the traditional alumina column technetium generator.
The most important characteristics of a high quality gel moly generator system are: (1) high elution efficiency
and (2) minimal Mo breakthrough. These two characteristics can only be achieved when the gel has a uniform
particle size. The gel can withstand thermal (wet steam) autoclaving; consequently, the generator can be provided
to radiopharmacies as a terminally sterilized finished product.
A more comprehensive description of gel moly generator system types and other technetium recovery
systems that use low specific activity
99
Mo is presented in Ref. [96].
6.3.4. High adsorption capacity column generator
Another form of generator takes advantage of the high capacity for molybdate ion on a new class of sorbants,
such as polymeric oxides of zirconium (PZC) [77, 97100] and titanium (PTC) [3, 77, 85].
Research is in progress at ANSTO [101] and in the Dalat Nuclear Research Institute (DNRI) on the use of
PTC and/or PZC as sorbent materials for radionuclide generator column loading [77]. The high adsorption capacity
of PTC and PZC sorbent for
99
Mo (270275 mg Mo/g) makes it suitable for obtaining
99m
Tc in patient dose
quantities with small columns and small eluate volumes. PZC/PTC sorbents (i.e. Nano-crystalline ZiSORB,
TiSORB, ZT-11 and ZT-31), when modified by further physicochemical treatments, can be used for different
radionuclide generator systems (e.g.
188
W).
A PZC/PTC based integrated radioisotope generator system is shown in Fig. 18 [102]. It consists of a
PZC/PTC sorbent column (housed in a lead container in the lower part of the system, behind the green sign);
FIG. 18. The integrated radioisotope generator system, recently developed at MEDISOTEC and ANSTO, is a radionuclide generator
system coupled with an automated purification/concentration unit [102].
34
a concentration/purification processing unit with a nuclide selective sorbent column (ZiSorb or ion exchange resin)
and eluent vials (upper part of the system); and a programmable control unit (bottom right). The programmable
electronic control unit allows the operator to specify the operating conditions for different integrated generator
systems for producing different radioisotopes such as
68
Ga,
99m
Tc and
188
Re [102].
6.3.5. Technetium radiolabelling
Technetium-99m radiopharmaceuticals are typically formulated from radiolabelling kits prepared in
manufacturing facilities that have an established GMP program. A cold kit contains: (1) the ligand to which
99m
Tc
is to be complexed, (2) a quantity of reducing agent, (3) a buffer to adjust the pH to suit the labelling conditions and
(4) stabilizing agents and excipients. The radiolabelling kits are prepared in a freeze dried state and have a shelf life
ranging from several months to years depending on the specific kit. There are 23 different radiolabelling kits
currently in use [103]. A typical cardiac perfusion imaging kit is shown in Fig. 19.
The compounding of
99m
Tc radiopharmaceuticals using radiolabelling kits in a hospital radiopharmacy is
routine. It involves the addition of [
99m
TcO
4
]
eluted from a generator, usually at room temperature, but at times

with heating.
The use of a chromatographic technique such as paper chromatography, ITLC, or HPLC is performed to
determine the radiochemical purity of the final product before it is administered to patients.
FIG. 19. Covidiens kit for the preparation of
99m
Tc sestamibi injection.
35
7. TECHNOLOGY READINESS TABLES
7

7.1. REACTOR BASED TECHNOLOGIES
Tables 69 present the technology readiness levels (TRL) for reactor based technologies.
7
The TRLs are defined in Appendix B.
TABLE 6. TRLs
7
FOR QUALIFICATION OF LEU AND MOLYBDENUM TARGETS
(n, f) target material TRL
Production scale
applicability
Comments
LEU in the form of dispersion mix, oxide, or metal
UAl
x
(2.6 3.0 gU/cc) 9 S, M, L
a
Targets currently manufactured by CERCA and CNEA;
Irradiated in Argentina, Australia, Egypt and South Africa.
U
3
Si
2
(4.8 gU/cc) 6/7 S, M, L Qualified fuel type for material and test reactors;
Evaluated by the NRC [12].
U
3
Si
2
(6.0 gU/cc) 6 S, M, L Capability to fabricate has been demonstrated by CERCA;
Not qualified as a fuel type for material and test reactors
(U-Loading > fuel qualification limit of 4.8 gU/cc)
U foil (19.0 gU/cc) 8 S, M Targets for small scale productionfabricated on-site by BATAN;
CERCA produced prototype targets for ANSTO.
5 L Targets not yet manufactured commercially;
Target qualification documentation does not yet exist;
Not yet irradiated to the burnup that is representative of a current major
99
Mo producer.
U nitride (7.0 gU/cc) 5/6 S, M, L Has been manufactured into mini-plates by CERCA;
No test irradiations performed to date.
U metal pellets/discs 8 S Targets have been fabricated using natural uranium and irradiated to
produce
99
Mo at CINR from 1963 to 1980 [24];
U oxide pellets/powder 8 S. L Pellets once used as target material (2.2% enrichment) to produce
99
Mo
at ANSTO;
Pellets used as target material (2.6% enrichment) to produce
99
Mo at
JAERI in 1977;
AECL developed HEU oxide powder (MAPLE reactor targets);
Original Cintichem process used HEU oxide targets.
a
S = small, M = medium, L = large.
36
LEU in the form of an aqueous solution (solution reactor fuel)
Uranyl nitrate (UO
2
(NO
3
)
2
5 L
a
Several experimental solution (HEU) reactors have been operated for
several minutes to several hours; not yet demonstrated at steady state
operation for long periods of time.
Uranyl sulphate (UO
2
SO
4
) 45 L Solution reactor technology not yet demonstrated using LEU fuel.
Molybdenum-98 oxide (MoO
3
)
Natural abundance (~24%) 9 S Currently in use throughout the world (e.g. India, Kazakhstan, Vietnam).
Enriched >95% 9 S 97% enriched material used in Uzbekistan;
Available in limited/small quantities at present.
Molybdenum-98 Metal
Natural abundance (~24%) 8 S Once used routinely prior to the advent of fission produced
99
Mo.
4 M, L Demonstration trials in progress at MURR.
Enriched >95% 4 S Available in limited/small quantities at present.
a
S = small, M = medium, L = large.
TABLE 6. TRLs
7
FOR QUALIFICATION OF LEU AND MOLYBDENUM TARGETS (cont.)
(n, f) target material TRL
Production scale
applicability
Comments
37

T
A
B
L
E

7
.

T
R
L
s

F
O
R

D
I
S
S
O
L
U
T
I
O
N

O
F

D
I
S
P
E
R
S
I
O
N

M
I
X
,

O
X
I
D
E

A
N
D

M
E
T
A
L

L
E
U

T
A
R
G
E
T
S
D
i
s
s
o
l
u
t
i
o
n

P
r
o
c
e
s
s
F
i
s
s
i
o
n

p
r
o
d
u
c
t
i
o
n

t
a
r
g
e
t

m
a
t
e
r
i
a
l
C o n v e n t i o n a l
a l k a l i n e
C o n v e n t i o n a l
a c i d i c
L E U m o d i f i e d
C i n t i c h e m
A l k a l i n e w /
a c i d i c f r o n t e n d
A l k a l i n e w /
e l e c t r o c h e m i c a l
f r o n t e n d
A l k a l i n e w /
f l u o r i d e f r o n t e n d
P y r o - p r o c e s s i n g
C
o
m
m
e
n
t
s
U
A
l
x

(
2
.
6
3
.
0

g
U
/
c
c
)
9
C
u
r
r
e
n
t
l
y

u
s
e
d

b
y

A
r
g
e
n
t
i
n
a
,

A
u
s
t
r
a
l
i
a
,

E
g
y
p
t

a
n
d

S
o
u
t
h

A
f
r
i
c
a
.
U
3
S
i
2

(
4
.
8

g
U
/
c
c
)
6
D
e
m
o
n
s
t
r
a
t
e
d

a
t

K
a
r
l
s
r
u
h
e
,

G
e
r
m
a
n
y
.
U
3
S
i
2

(
6
.
0

g
U
/
c
c
)
2
N
o
t

y
e
t

d
e
m
o
n
s
t
r
a
t
e
d

t
o

w
o
r
k

w
i
t
h

u
r
a
n
i
u
m

l
o
a
d
i
n
g

o
f

6
.
0

g
U
/
c
c
.
U

f
o
i
l

(
1
9
.
0

g
U
/
c
c
)
4
8
4
3
x
a
L
E
U

M
o
d
i
f
i
e
d

C
i
n
t
i
c
h
e
m

p
r
o
c
e
s
s

w
a
s

d
e
v
e
l
o
p
e
d

t
o

p
r
o
d
u
c
e

9
9
M
o

a
t

s
m
a
l
l

s
c
a
l
e

(
B
A
T
A
N
)
;
C
i
n
t
i
c
h
e
m

u
s
e
d

a

s
i
m
i
l
a
r

p
r
o
c
e
s
s

w
i
t
h

H
E
U

o
n

a

l
a
r
g
e

s
c
a
l
e
.
U

n
i
t
r
i
d
e

(
7
.
0

g
U
/
c
c
)
2
U

m
e
t
a
l

p
e
l
l
e
t
s
/
d
i
s
c
s
x
x
8
x
1
A
l
k
a
l
i
n
e

w
i
t
h

a
c
i
d
i
c

f
r
o
n
t

e
n
d

u
s
e
d

i
n

t
h
e

1
9
8
0
s

f
o
r

d
i
s
s
o
l
v
i
n
g

i
r
r
a
d
i
a
t
e
d

n
a
t
u
r
a
l

u
r
a
n
i
u
m

(
N
U
)

p
e
l
l
e
t
s

f
o
r

s
m
a
l
l

s
c
a
l
e

m
o
l
y

p
r
o
d
u
c
t
i
o
n

a
t

C
I
N
R
.
U

o
x
i
d
e

p
e
l
l
e
t
s
/
p
o
w
d
e
r
8
x
O
n
c
e

u
s
e
d

a
t

A
N
S
T
O

(
2
.
2
%

e
n
r
i
c
h
m
e
n
t
)
;
A
E
C
L

d
e
v
e
l
o
p
e
d

a

p
r
o
c
e
s
s

f
o
r

d
i
s
s
o
l
v
i
n
g

H
E
U

o
x
i
d
e

p
o
w
d
e
r

(
M
A
P
L
E

r
e
a
c
t
o
r

t
a
r
g
e
t
s
)
;
C
i
n
t
i
c
h
e
m

p
r
o
c
e
s
s

u
s
e
d

H
E
U

o
x
i
d
e

t
a
r
g
e
t
s
.
a
x

=

p
o
t
e
n
t
i
a
l
l
y

a
p
p
l
i
c
a
b
l
e

b
u
t

u
n
t
r
i
e
d

p
r
o
c
e
s
s
38
TABLE 8. TRLs FOR DISSOLUTION OF LEU AQUEOUS SOLUTION TARGETS
Dissolution process
Solution reactor
target material
9
9
M
o

r
e
c
o
v
e
r
y
9
9
M
o

p
u
r
i
f
i
c
a
t
i
o
n
(
C
i
n
t
i
c
h
e
m
)
9
9
M
o

p
u
r
i
f
i
c
a
t
i
o
n
(
c
o
n
v
e
n
t
i
o
n
a
l

a
l
k
a
l
i
n
e
)
9
9
M
o

p
u
r
i
f
i
c
a
t
i
o
n
(
K
u
r
c
h
a
t
o
v
)

p
r
o
c
e
s
s
Comments
UO
2
(NO
3
)
2
4 4 4 x INVAP is developing this technology.
UO
2
SO
4
x x x 4 Kurchatov demonstrated conventional acidic process for HEU.
TABLE 9. TRLs FOR DISSOLUTION, SEPARATION AND POST-ELUTION CONCENTRATION OF
MOLYBDENUM TARGETS
Target Material
Process
Oxide (MoO
3
) Metal
Comments
Natural Enriched Natural Enriched
D
i
s
s
o
l
u
t
i
o
n
Alkaline 9 9 3 3
Acidic x x x x
Peroxide 3 3 See Ref. [41]
Electrochemical 3 3 See Ref. [40]
9
9
m
T
c

g
e
n
e
r
a
t
o
r
Electrochemical 2 See Ref. [104]
Recoil 1 1 x
Based on Delft Papers/patent using organometalic target
compounds.
Sublimation 8 x x x Performed in Australia and Hungary.
ZrMoO
4
gel 9 9 x x Performed in China, Kazakhstan, Uzbekistan and Vietnam.
TiMoO
4
gel 2 x x x R&D in India and Vietnam.
PZC 6 x x x R&D in Australia, Japan and Vietnam.
PTC 3 x x x R&D in Australia, India and Vietnam.
Ion exchange 4 x 4 4
For natural MoO
3
. Based on Ref. [105] and the agreed
potential application of Northstars development work.
Solvent extraction 9 9 9 9 Performed in Australia, India and Vietnam [106].
Post-elution concentrators
6 6 6 6 R&D in Australia, India, USA and Vietnam.
39
7.2. ACCELERATOR BASED TECHNOLOGIES
Tables 1014 present the TRLs for accelarator based technologies. The levels are based on information
supplied, on what has appeared in the literature as well as extrapolation from what has been achieved in other areas
that can be directly applied to the present problem. For example, where one of the technologies produces
99
Mo

via
fission of
235
U, one can assume that the technology for isolating the
99
Mo

from the LEU target mix would be
identical to that being used in the reactor facilities. However, this does not mean that the proponents for the
particular approach have the necessary skill sets to implement such approaches without the input from experienced
partners that may include proprietary information. TRLs are defined in Appendix A.
No attempt has been made to determine the technology readiness of any particular proponent, since this will
in all likelihood be a constantly changing metric as efforts move forward with greater or lesser efficiency
throughout the world.

TABLE 10. PHOTONEUTRON, (,n), TRANSFORMATION OF
100
Mo
(classified as medium capacity for a single device)
Technology TRL Comment
Accelerator 6 Concept well established, requires development for high power
Targetry 3 Enriched target, development work needed
Processing 5 Prototype exists, in clinical trials for other radioisotopes
Production of
99m
Tc generators 5 See above
Waste management 4 Minimal waste, although tracking of
99g
Tc and non-moly isotopes required
Regulatory approval:
Nuclear
Health
7
5
Extensive testing required
The technology is rated overall as 4.
TABLE 11. DIRECT PRODUCTION OF
99m
Tc VIA
100
Mo(p,2n) REACTION
(classified as small capacity for a single device)
Accelerator 89 Use of existing cyclotrons; proposed new cyclotron not field tested
Targetry 4 Under development
Processing 4 Working at lab scale
Production of
99m
Tc generators n/a Not used; the
99m
Tc is distributed directly from the cyclotron centre
Waste management 4 Minimal, tracking of
99g
Tc required
Nuclear
Health
9
5
Cyclotrons have been reviewed by nuclear regulatory authorities for this process
Extensive testing required to validate the quality of
99m
Tc produced
40

TABLE 12. HIGH ENERGY PROTON FISSION OF
238
U
(classified as large capacity for a single device)
Accelerator 2 CW high energy driver (200 MeV, 100 kW); ideas are well documented; theoretical
calculations have been performed and are available. However, no confirmation is available
regarding laboratory prototype testing which demonstrates proof of principle.
Targetry 2 Target composition is still being evaluated. Even if composition of the target will be similar
to the standard LEU reactor fuel, there is no available report on laboratory prototype testing
which demonstrates proof of principle of this concept.
Processing 4 Most of the U type materials have been tested in dissolution processes but not all are related
to
99
Mo

production. Therefore information is available but it may not be complete.
Production of
99m
Tc generators 9 Assuming that the processing of the U target is fully developed and the
99
Mo

contamination
profile and specific activity follows the current standard specification for fission
99
Mo, the
current alumina based
99m
Tc generators can be used without any modification or licence change.
Waste management 2 Management of the processing waste streams may be known but has not yet been tested on the
laboratory scale to demonstrate proof of principle for this type of
99
Mo

technology.
Nuclear
Health
1
78
This technology is new for the regulators, since there is no operational device currently
running. The regulatory approval process must first be developed and will be lengthy.
The
99
Mo

contamination profile and specific activity follows the current standard
specification for fission
99
Mo. The product would only need to be tested in three production
runs to confirm the repeatability of final product quality. In some States the final product
quality can be related to both nuclear isotopes:
99
Mo, Tc
99m
/
99g
Tc.
TABLE 13. LOW ENERGY PRODUCTION OF NEUTRONS VIA (d,t) OR D(,n)H REACTIONS FOLLOWED
BY FISSION USING LEU
(production capacity rating: medium single device or a cluster of devices would meet national needs)
Accelerator
(D,T)
(,n)
3
6
Under development, prototypes exist
Concept well established, requires development for high power
Targetry 6
3
Production targets for both methods exist but need development
Would use LEU targets
Processing 5 Similar to existing fission process
Production of
99m
Tc generators 3 Product is expected to meet USP specifications and be of high specific activity so that it can
be used directly in existing commercial generator systems
Waste management 3 Extensive, similar to existing fission process
Nuclear
Health
5
6
A representative model or prototype system has been tested (ARGUS). Regulatory concern
will focus on the stated subcritical nature of the system and system design features which will
assure that it will remain subcritical.
Product is expected to meet USP specifications based on ARGUS experience if these results
can be confirmed.
41
8. CONCLUSION
The information in this report, including Tables 614 and the cited references, gives an indication as to the
TRL for each of the technical approaches described in the preceding sections. Determinations of TRLs were based
on information supplied by technology developers, information available from the literature and also from
extrapolations from other technologies. With respect to extrapolation, one can assume, for example, that processes
for isolating
99
Mo

from a uranium target will be similar regardless of whether the target was irradiated in a reactor
or an accelerator. The TRLs shown in the tables are neither judgements nor endorsements of any particular
technology developing organization.
TABLE 14. POST-PRODUCTION ENRICHMENT OF
99
Mo VIA OFF-LINE ISOTOPE SEPARATOR
(classified as medium capacity for a single device)
Technology
TRL
Comment
Accelerator 45 Prototype exists
Targetry n/a Supplied from existing systems
Processing 45 Minimal changes to the chemical form of the collected material required
Production of
99m
Tc generators 9 Uses existing technology
Waste management 4 Minimal, track
99g
Tc
Nuclear
Health
4
8
Operation of separator with large quantities of radioactivity will require development of
remote handling systems
Expected to be straightforward
.
43
Appendix A
TECHNOLOGY READINESS LEVELS (TRLs) AND THEIR DEFINITIONS
The following list describes the various technology readiness levels and descriptions from a systems approach
for both hardware and software.
Technology readiness level (TRL) description
TRLs are used in private industry and in many government agencies to guide technology investment,
development and deployment. Examples of several TRL systems used in various applications are provided in
Refs [107109]. The TRL definitions used in this report were tailored from Refs [108] and [109].
Industry recognized product development methodologies are used to some extent in all major industries. They
are used to ensure that the technology required to deploy a product to market is consistent with the products
business development model. These methodologies provide a common language to describe the extent to which the
product design is complete. They also provide a guide for the designers of a manufacturing or production process to
follow, allowing them to focus only on the tasks defined for a given development level. This prevents superfluous
studies that do not contribute to the advancement of the products technology. Furthermore, it provides assurance
that the products business development model is both practical and economically viable. The rationale for TRLs is
that they provide a metric for measuring technical maturity and communicating readiness of the product for each
phase of a project. In summary, a technology readiness assessment simply establishes the maturity of a specific
technology.
Numerous studies performed in the USA for both private industry and the federal government have concluded
that the insertion of immature technologies and/or immature manufacturing systems increases risk and cost and
significantly decreases the likelihood of successful implementation.
For the purpose of this document, a TRA has been performed using established TRL requirements or
milestones. Each non HEU
99
Mo

production technology is evaluated against the TRL requirements. The established
TRL scale ranges from 1 to 9 and is presented in Fig. 20. The TRLs progress from research and development
activities to design validation in a production environment. The TRL assignment is a snapshot of where the
maturity of the technology is at a given point of time. It should represent the highest level of TRL for which all the
exit criteria are satisfied.
It should be noted that there is an associated methodology that defines manufacturing readiness levels [110].
A manufacturing readiness assessment is performed in conjunction with a TRA to make a final determination of the
overall readiness level of a non HEU
99
Mo

production technology. Manufacturing readiness assessment is a critical
prerequisite of a project, but is beyond the scope of this report. A more comprehensive explanation of TRLs 19 is
presented below.
TRL definitions and Exit Criteria
TRL 1 Lowest level of technology readiness. Scientific research begins to be translated into a concept for a
technology.
Exit Criteria (1) A fundamental concept, innovation or scientific principle has been identified.
TRL 2 Practical applications are beginning to be identified or developed. There is no proof or detailed
analysis to support assumptions. The step up from TRL 1 to TRL 2 moves the concept from pure to applied
research. Experimental work is designed to corroborate the basic scientific observations made during TRL 1 work.
The filing of a patent is under consideration.
Exit Criteria (1) Potential practical applications for this research and/or innovation are identified. An R&D
plan has been developed.
TRL 3 Active research and development (experiments, simulations) is initiated to validate key elements of
the technology. The results of this work should constitute proof of concept validation of the applications and
concepts formulated at TRL 2. Examples include the study of separate elements of the technology that are not yet
integrated or representative. At TRL 3 the work has moved beyond the paper phase to experimental work that
verifies the concept as anticipated. Components of the technology are validated, but there is no attempt to integrate
44
the components into a complete system. Modelling and simulation may be used to complement physical
experiments.
Exit Criteria (1) Key elements of the technology have been identified and proof of concept has been
demonstrated for each. Individual elements are not necessarily integrated at this technology readiness level.
TRL 4 The key elements of the technology are integrated (i.e. elements will function together) in the
laboratory. TRL 4 is the first step in determining whether the individual components will work together as a system.
Exit Criteria (1) A laboratory validation establishes that key elements function together; validation in a
laboratory environment can be made with mock material and (2) performance metrics for the laboratory prototype
have been defined and met.
TRL 5 Key elements of the technology are integrated with applicable supporting elements so that the system
can be tested in a simulated or somewhat realistic environment. The major difference between TRL 4 and 5 is the
increase in the fidelity of the system and environment to the actual application. The system tested is almost
prototypical.
Exit Criteria (1) Validation in a simulated or somewhat realistic environment establishes that the key elements
function together and (2) performance metrics have been defined and met.
TRL 6 A system or subsystem prototype is demonstrated in a high fidelity, simulated or actual environment.
This represents a major step in a technologys demonstrated readiness.
Exit Criteria (1) A prototype has been created and successfully demonstrated in a high fidelity, simulated or
actual environment and (2) the metrics for successful performance in an actual environment have been refined, met
and documented. TRL 6 begins true engineering development of the technology as an operational system. The
major difference between TRL 5 and 6 is the step up from laboratory scale to engineering scale and the
determination of scaling factors that will enable design of the operating system.
TRL 7 Demonstration of an actual system prototype in an operational environment. In almost all cases,
TRL 7 coincides with the end of development.

TRL 1
Basic principles
observed and reported
TRL 2
Concept and/or
application formulated
TRL 3
Concept demonstrated by
analysis and/or experiment
TRL 4
*
Key elements demonstrated in
laboratory environment
TRL 5
*
Key elements demonstrated in
relevant environment(s)
TRL 6
*
Representative deliverable
demonstrated in relevant environment
TRL 7
Final development demonstrated
in operational environment
TRL 8
Product qualified
by test and/or demonstration
TRL 9
Product manufacture is routine
and quality level is repeatable
Research activities Development activities Manufacturing activities
* TRLs 4 6 represent the bridge from scientific research to process design development.
FIG. 20. TRL element identification and activity type.
45
Exit Criteria (1) An actual system prototype has been demonstrated in an operational environment and (2) the
metrics for successful performance in operational environments have been refined, met and documented.
TRL 8 The actual system has been proven to work in its final form under expected conditions based on
certification and qualification activities to validate that it meets design requirements, product definition and quality
requirements.
Exit Criteria (1) A manufacture system has been certified/qualified.
TRL 9 The system is implemented in its final form. The system is fully developed and currently operational.
TRL 9 does not consider ongoing or planned product improvement, or scale up to larger production volumes.
.
47
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[93] EVANS, J.V., MOORE, P.W., SHYING, M.E. SODEAU, J.M., Zirconium molybdate gel as a generator for technetium-99m,
Appl. Radiat. and Isotopes 38 (1987).
[94] BOYD, R.E., The gel generator: a viable alternative source of technetium-99m for nuclear medicine, Appl. Radiat. and Isotopes
48 (1997) 10271033.
[95] LE VAN SO et al., Preparation of inorganic polymer sorbents and their application in radionuclide generator technology,
Therapeutic Radionuclide Generators:
90
Sr/
90
Y and
188
W/
188
Re Generators, IAEA Technical Report Series No. 470,
(INTERNATIONAL ATOMIC ENERGY AGENCY, Ed.), (2009) Ch 20.
[96] INTERNATIONAL ATOMIC ENERGY AGENCY, Alternative technologies for
99m
Tc generators, IAEA-TECDOC-852,
IAEA, Vienna (1995).
[97] HASEGAWA, et al., Mo adsorbent for
99
Mo-
99m
Tc generators and manufacturing thereof, U.S. Patent 5,681,974, October 28,
1997.
[98] SARASWATHY, P., DEY, A.C., et al. (BRIT), VENKATESH. M. and VENUGOPAL, V. (BARC), RAMAMOORTHY, N.
(IAEA), Tc-99m Generators for Clinical Use Based on Zirconium Molybdate Gel and (n,) Produced Mo-99: Indian
Experience in the Development and Deployment of Indigenous Technology and Processing Facilities, Proc. Int. RERTR Mtg.,
2007, RERTR, Argonne, IL (2007).
[99] OSSO JUNIOR, J.A., LCIA, A., LIMA, V.P., et al., Preparation of a gel of zirconium molybdate for use in the generators of
99
Mo
99m
Tc prepared with
99
Mo produced by the 98Mo(n,g )
99
Mo reaction, Proc. Int. RERTR Mtg Sao Paulo, 1998,
RERTR, Argonne, IL (1998).
[100] TANASE, TATENUMA, ISHIKAWA, et al., A
99m
Tc Generator using a New Inorganic Polymer Adsorbent for (n, )
99
Mo,
Appl. Radiat. and Isotopes 48, 5 (1997) 607611.
[101] ANSTO, Radionuclide development web page,
http://www.ansto.gov.au/research/lifesciences/current_research/radionuclide_development, ANSTO, accessed 10 October
2012.
[102] VAN SO LE,
68
Ga generator integrated system: elutionpurificationconcentration integration, Recent Res. Cancer 194, (2013)
4375.
[103] INTERNATIONAL ATOMIC ENERGY AGENCY, Technetium-99m Radiopharmaceuticals: Manufacture of Kits, IAEA
Technical Report Series No. 466, IAEA, Vienna (2008).
[104] CHAKRAVARTY, R., DASH, A., VENKATESH, M., A novel electrochemical technique for the production of clinical grade
99mTc using (n, gamma)99Mo, Nucl. Med. Biol. 37 1 (2010) 218.
[105] SARKAR, S. K., ARJUN, G., SARASWATHY, P., RAMAMOORTHY, N., Post-elution concentration of 99TcmO4- by a single
anion exchanger column: II. Preparation and evaluation of jumbo alumina column chromatographic generator for 99Tcm, Nucl.
Med. Commun. 22 4 (2001) 38997.
51
[106] CHATTOPADHYAY, S., BARUA, L., DE, A., SAHA DAS, S., KUNIYIL, R., BHASKAR, P., PAL, S.S.,
KUMAR SARKAR, S., DAS, M.K., A computerized compact module for separation of (99m)Tc-radionuclide from
molybdenum, Appl Radiat. Isot. 70 11 (2012) 26317.
[107] SOLBREKKEN, G., TURNER, K., ALLEN, C., Engineering of LEU-Foil Based Mo-99 Target for High Volume Production,
Proc. RERTR 31st Int. Mtg on Reduced Enrichment for Research and Test Reactors Beijing, China, 2009, RERTR, Argonne,
IL (2009).
[108] UNITED STATES DEPARTMENT OF ENERGY, Technology Readiness Assessment Guide, DOE G 413.3-4, Office of
Management, Washington, DC (2009).
[109] UNITED STATES DEPARTMENT OF DEFENSE, Technology Readiness Assessment (TRA) Deskbook, Director, Research
Directorate (DRD), Office of the Director, Defense Research and Engineering (DDR&E), Washington, DC (2009).
[110] MANKINS, J.C., Technology Readiness Levels: A White Paper, Advanced Concepts Office, Office of Space Access and
Technology, NASA, USA (1995).
.
53
GLOSSARY
6 day curie (Ci) (gigabecquerels - GBq). The quantity of
99
Mo

available for sale from an irradiated target is much
less than the total quantity of
99
Mo

produced in the target because of radioactive decay and process losses.
Standard industry practice is to sell bulk
99
Mo

on the basis of a calibrated 6 day curie, which is nominally the
quantity of
99
Mo

remaining 6 days after the
99
Mo

leaves the producers facility.
99
Mo has a 65.94 hour
half-life. To have one curie (37 gigabecquerels) remaining after six days of decay, a producer must ship
4.54 Ci (168 GBq). The production cycle of
99
Mo illustrating growth during irradiation followed by losses
due to chemical processing and radioactive decay is presented below.
activity concentration (also called radioactivity concentration). For technetium-99m (
99m
Tc), it is the activity of
99m
Tc in a sample expressed in Ci (GBq) divided by the volume expressed in millilitres (mL) of the sample at
a specified reference calibration date and time.
barn. Symbol (b), is a unit of measurement. The neutron interaction with the nucleus of a target material can be
quantitatively expressed in terms of the nuclear cross-section, which is a measure of the probability that the
given reaction takes place. The unit of cross-section is a barn (1 barn = 10
24
cm
2
). The value of the cross-
section varies with the energy of the neutrons and from nucleus to nucleus. In general, the slower the neutron,
the greater the probability for the reaction to occur.
bequerel. Symbol (Bq), is the SI derived unit of radioactivity. One Bq is defined as the activity of a quantity of
radioactive material in which one nucleus decays per second. The Bq unit is therefore equivalent to s
1
. 1 Bq
2.70 10
11
curie. A gigabecquerel (GBq) is a billion becquerels. 1 GBq = 10
9
Bq 2.70 10
2
curie.
burnup. The amount, expressed in percent (%), of the
235
U atoms in a target that fission during irradiation. For
targets irradiated at a thermal neutron flux of greater than 2.0E14 n/cm
2
-s and irradiated for 200 hours or
more, burnup will be in the range of 912%.
chromatographic recovery of
99m
Tc. The method of eluting
99m
Tc from a chromatographic column. The column
material is traditionally made of alumina (Al
2
O
3
). Column materials other than alumina can be used, such as
titanium dioxide or zirconium dioxide. Column chromatography in chemistry is a method used to separate an
individual compound (or isotope) from a mixture of compounds (or isotopes).
curie. Symbol (Ci), is a older unit of radioactivity, defined as the radioactivity in 1g of pure radium 226.
1 Ci = 3.7 10
10
decays per second (= 3.7 10
10
Bq).
Figure G-1.
99
Mo production and decay timeline (typical).
54
eluate. The effluent exiting a chromatographic bed when elution is performed.
eluent (or eluant). The liquid or gas entering a chromatographic bed that is used to effect a separation by elution.
For the recovery of
99m
Tc, the eluent is normal saline.
elution efficiency. The fraction, expressed in percent (%), of
99m
Tc on the column at the time of elution that is
stripped from the column by the eluent. For conventional generators this is typically about 85%. Elution
efficiency is also referred to as recovery efficiency.
epithermal neutron. A neutron having an energy in the range of 1.010 keV. Refer to thermal neutron for
comparison.
half-life. The time required for a quantity of radioactive material to decay to one half of its original value.
heterogeneous reactor. A nuclear reactor in which the fuel is separated from the moderator.
homogeneous reactor. A nuclear reactor in which the fuel is mixed with the moderator or coolant. An example of
a liquid homogenous reactor is uranium sulphate in water.
key elements. Components/pieces of a technology that are integrated into a process so that the technology meets
the customer requirements agreed upon. Identification of key elements involves understanding the functional
aspects of a technology as well as how they will be developed.
large scale producer.
1
Has the processing capability to produce greater than 1000 6 day curies (37 000 6 day
gigabecquerels) per week of
99
Mo on a routine basis. A large scale producer has the necessary shipping
infrastructure in place to transport the finished product internationally on a routine basis.
liquidliquid extraction. Chemical separation method used to recover
99
Mo. Also known as solvent extraction. It
is a method to separate compounds based on the relative equilibrium concentrations of two different
immiscible liquids in contact, usually water and an organic solvent. It is the extraction (recovery) of a
substance from one liquid phase into another liquid phase.
medium scale producer.
2
Has the processing capability to produce in the range of 200 to 1000 6 day curies (7400 to
37,000 6 day gigabecquerels) per week of
99
Mo on a routine basis. A medium scale producer typically supplies
a specific regionally based market and has the necessary shipping infrastructure in place to transport the
99
Mo
finished product to its established regional market. Regionally based includes neighbouring countries.
molybdenum-99/technetium-99m production cycle. Regardless of the mode of production of
99
Mo, the relative
quantities of
99
Mo

and
99m
Tc remain the same for any particular production cycle and decay period during
processing and shipment. The 6 day curie concept is schematically illustrated in Figure G-1, which shows the
buildup and decay of
99
Mo

during target irradiation, processing and shipping. During the 512 day period of
irradiation in the reactor (left side of figure),
99
Mo

builds up in the target and eventually approaches a
maximum as
99
Mo

production is balanced by
99
Mo

loss to radioactive decay.
99
Mo

continues to be lost to
radioactive decay after the targets are removed from the reactor and some additional losses are incurred
during target processing because of process inefficiencies (middle of figure). The amount of
99
Mo

available
1
Magnitude established by the National Research Council of the National Academies (COMMITTEE ON MEDICAL ISOTOPE
PRODUCTION WITHOUT HIGHLY ENRICHED URANIUM, NATIONAL RESEARCH COUNCIL OF THE NATIONAL
ACADEMIES, Medical Isotope Production Without Highly Enriched Uranium, The National Academies Press, Washington DC (2009)).
2
Definition should not be construed as being absolute. The purpose of defining production scale levels in this document is to
qualitatively compare the manufacturing capability of the various production technologies under development or currently deployed to
produce
99
Mo. In essence, the definition is used for the benchmarking of a one producers production capability against anothers.
55
for sale as 6 day curies (right side of figure) is only a fraction of the isotope present in the targets at the end-of-
bombardment (EOB) by neutrons during irradiation in the reactor.
99
Mo

6 day curies represent the number of
curies present in a shipment of
99
Mo

6 days after it leaves the producers facilities.
natural molybdenum (Mo). Of all the stable molybdenum isotopes,
98
Mo is the most abundant, comprising 24.1%
of all natural molybdenum. As such,
98
Mo is said to have a natural abundance (NA) of 24.1%. The other stable
isotopes of natural molybdenum are: (1)
92
Mo; 14.8% NA, (2)
94
Mo; 9.3% NA, (3)
95
Mo; 15.9% NA,
(4)
96
Mo; 16.7% NA, (5)
97
Mo; 9.5% NA and (6)
100
Mo; 9.6% NA. Because
100
Mo has an extremely long half-
life (>10
8
years), it is considered to be a stable isotope of natural molybdenum.
polymeric titanium-oxychloride or polymeric titanium compound (PTC). Sorbent material developed and
proposed for use in neutron activation (n-gamma)
99
Mo based
99m
Tc generators [3, 77, 85]. This titanium
based inorganic polymer exhibits both excellent
99
Mo adsorption capacity and
99m
Tc elution. The main
constituents of this sorbent material are titanium, oxygen and chlorine. The adsorption capacity of PTC for
99
Mo is reported to be higher than that of conventional alumina.
polymeric zirconium-oxychloride or polymeric zirconium compound (PZC). Sorbent material used in neutron
activation (n-gamma)
99
Mo based
99m
Tc generators. This zirconium based inorganic polymer exhibits both
excellent
99
Mo adsorption capacity and
99m
Tc elution [77, 95, 97]. The main constituents of this sorbent
material are zirconium, oxygen and chorine. The adsorption capacity of PZC for
99
Mo is reported to be higher
than that of conventional alumina.
post-elution concentrator. Used for low specific activity
99
Mo. The eluate of the technetium recovery system is
passed through a chromatography column (i.e., concentrator). The concentration column is then stripped
using normal saline. This two stage recovery process increases the final activity concentration of the
99m
Tc.
production strategy. The high level sequence of steps that will be used to produce an item. The production strategy
is intended to be of sufficient detail to be able to develop a cost and schedule.
readiness level. A measure of technology and manufacturing system maturity.
small scale producer. Has the processing capability to produce up to 200 6 day curies (7400 6 day gigabecquerels)
per week of
99
Mo on a routine basis to a geographically local
99m
Tc generator manufacturer.
specific activity. For molybdenum-99 (
99
Mo), it is the activity of the
99
Mo in a sample expressed in curies (Ci)
(gigabecquerelsGBq) divided by the total mass, expressed in grams, of the elemental molybdenum in the
sample at a specified reference calibration date and time.
solvent extraction (or recovery). See liquidliquid extraction.
sublimation. Is the transition of a substance from the solid phase to the gas phase without passing through an
intermediate liquid phase.
target. For fission product
99
Mo, this consists of a target meat that is encapsulated by a cladding. For neutron
activation (n-)
99
Mo consists of encapsulated molybdenum trioxide (MoO
3
) powder or a pressed sintered
molybdenum metal wafer. For accelerator produced
99
Mo, targets consist of molybdenum metal disks. For
direct production, metal foils or plating of enriched Mo on various substrate materials is being explored.
target cladding. Serves to protect the reactive uranium metal or alloy target meat and provides the barrier that
prevents the release of solid and gaseous fission products produced during target irradiation. The target
cladding material is typically aluminium.
56
target meat. The uranium bearing material in a fission product
99
Mo production target. The target meat can be in
the form of U-Al alloy, UAl
x
-Al dispersion matrix, UO
2
, or U metal.
Technology readiness assessment (TRA). An industry recognized method used to assess the technology readiness
of a product under development. It is formal, systematic and metric based. The metrics are defined by the
TRLs. A TRA: (1) provides a common language to communicate the maturity of a technology, (2) enables a
disciplined approach to evaluate technology readiness and (3) provides an effective tool and metrics to assess
technology risk. It is simply an analysis for determining the technology maturity with respect to meeting
product realization goals.
Technology readiness level (TRL). A metric used for describing technology maturity. It is a measure to assess the
maturity of evolving technologies (materials, components, devices, etc.) prior to incorporating that
technology into a system or subsystem. TRLs focus on a technologys maturity and are designed to measure it
and indicate what has been accomplished in the development of that technology.
thermal neutron. A neutron having an energy of about 0.025 eV at 20C. Refer to epithermal neutron for
comparison.
UAl
x
dispersion target. For HEU Al
x
dispersion targets, the target meat begins as a blend of UAl
x
powder made of
UAl
2,
UAl
3
and UAl
4
intermetallics and pure aluminium powder. For LEU Al
x
dispersion targets, the target
meat begins as a blend of UAl
2
and pure aluminium powders. During the hot rolling and annealing steps in
fabricating a
99
Mo production target, all of the UAl
2
reacts with aluminium in the target meat matrix to form
UAl
3
and some of the UAl
3
reacts with aluminium to form UAl
4
. Thus, the target meat of a finished target
contains both UAl
3
and UAl
4
. The actual fractions of UAl
3
and UAl
4
in a finished dispersion target will vary
from manufacturer to manufacturer depending on the processes and heat treatments that are utilized in
fabricating the powder, core compacts and target plates.
Uranium loading. The mass of uranium per cm
3
of the target meat. It is sometimes referred to as U density.
US Pharmacopeia (USP). Is the official pharmacopoeia of the United States, published dually with the National
Formulary (NF) as the USP-NF. It establishes written (documentary) and physical standards for medicines,
food ingredients, dietary supplement products and ingredients. These standards are used by regulatory
agencies and manufacturers to help to ensure that products are of the appropriate identity, as well as strength,
quality, purity and efficacy. Many other countries use the USP-NF instead of issuing their own
pharmacopoeia, or to supplement their government pharmacopoeia.
57
ABBREVIATIONS
ABEC aqueous biphasic extraction chromatographic
AECL Atomic Energy of Canada Limited
AHR aqueous homogeneous reactor
AMIC Advanced Medical Isotope Corporation
ANSTO Australian Nuclear Science and Technology Organisation
AREVA/CERCA Compagnie pour letude et la ralisation de combustibles atomiques, France
Argonne Argonne National Laboratory, USA
ARI ANSTO Radiopharmaceuticals and Industrials, Australia
BARC Bhabha Atomic Research Centre, India
BATAN National Nuclear Energy Agency, Indonesia
BRIT Board of Radiation and Isotope Technology, Mumbai, India
BR2 Belgian Reactor-2, SCKCEN Centre, Belgium
B&W Y-12 Babcock & Wilcox, USA
CCHEN Chilean Nuclear Energy Commission
CEA French Alternative Energies and Atomic Energy Commission
CINR Central Institute for Nuclear Research Rossendorf, Germany
CNEA National Atomic Energy Commission, Argentina
DNRI Dalat Nuclear Research Institute, Vietnam
EOB End of Bombardment (synonymous with End of Irradiation (EOI)
FDA Food and Drug Administration, USA
GMP good manufacturing practices (also cGMP, current good manufacturing
practices)
GSG Gamma-Service Group International
HEU high enriched uranium, uranium enriched in the isotope
235
U to 20% or more
HLG-MR High-level Group on Security of Supply of Medical Radioisotopes
HPLC high performance liquid chromatography
ICP-MS inductively coupled plasma mass spectrometry
INL Idaho National Laboratory, USA
INR Institute for Nuclear Research Pitesti reactor facility, Romania
INVAP Investigaciones Aplicadas S.E. INVAP, Argentina
IPEN Nuclear and Energy Research Institute, Brazil
IRE Institute for Radioisotopes, Belgium
ITLC instant thin layer chromatography
JAEA Japan Atomic Energy Agency
JAERI Japan Atomic Energy Research Institute
JRR Japan Research Reactor
KAERI Korea Atomic Energy Research Institute
KfK Institut fr Radiochemie Kernforschungszentrum Karlsruhe, GmbH, Germany
LANL Los Alamos National Laboratory, USA
LBNL Lawrence Berkeley National Laboratory, USA
LEU low enriched uranium, uranium enriched in the isotope
235
U to less than 20%
LMI Lantheus Medical Imaging, Massachusetts, USA
MAPLE Multipurpose Applied Physics Lattice Experiment reactor, Canada
MEK methyl ethyl ketone
MIPS medical isotope production system
MTR materials testing reactor
MU University of Missouri, USA
MURR University of Missouri Research Reactor, USA
NA natural abundance
NAS National Academy of Sciences, USA
58
NDA new drug application
OECD/NEA OECD Nuclear Energy Agency
Necsa-NTP Nuclear Energy Corporation of South Africa Nuclear Technology and
Products division
NRC Nuclear Regulatory Commission, USA
NRG Nuclear Research and Consultancy Group, Netherlands
NRU National Research Universal reactor, Canada
NU natural uranium
OPAL Reactor Open Pool Australian Light Water Reactor
ORNL Oak Ridge National Laboratory, USA
PINSTECH Pakistan Institute of Nuclear Science and Technology
PNL Phoenix Nuclear Laboratory, USA
POLATOM Institute of Atomic Energy, Radioisotope Centre, Poland
PUI Peaceful Uses Initiative (IAEA)
RERTR Reduced Enrichment for Research and Test Reactors program
ROSATOM State Atomic Energy Corporation Rosatom, Russian Federation
SCKCEN Belgian Nuclear Research Centre
TRIUMF TRI-University Meson Facility, Canada
USP United States Pharmacopeia
59
CONTRIBUTORS TO DRAFTING AND REVIEW
Abrams, D.N. Edmonton Radiopharmaceutical Centre, Canada
Adelfang, P. International Atomic Energy Agency
Alldred, K. International Atomic Energy Agency
Allen, C.W. University of Missouri Research Reactor Center, USA
Barbosa, L.A.M.M. Covidien Pharmaceuticals, Netherlands
Binder, J.L. Oak Ridge National Laboratory, USA
Bradley, E. International Atomic Energy Agency
Bryan, C. Oak Ridge National Laboratory, USA
Chakrov, P. Institute of Nuclear Physics, Kazakhstan
Chopard, F. AREVA (TA), France
Crowley, K. The National Academies, USA
DAubin, P.A. MDS Nordion, Canada
Goldman, I.N. Lantheus Medical Imaging, USA
Hamilton, R. Department of Energy, USA
Hobbs, R. Oak Ridge National Laboratory, USA
Ireland, J.R. Los Alamos National Laboratory, USA
Jaroszewicz, J.W. Institute of Atomic Energy, Poland
Lacey, M.J. Department of Energy, USA
Lokhov, A. OECD Nuclear Energy Agency, France
Moyaux, D. Institute for Radioelements, Belgium
Ramamoorthy, N. Bhabha Atomic Research Centre, India
Ruth, T.J. TRIUMF, Canada
Staples, P. Department of Energy, USA
Vandegrift, G. Argonne National Laboratory, USA
Vanderhofstadt, J.-M. Institute for Radioelements, Belgium
Consultants Meetings
Vienna, Austria: 1719 March 2010, 29 February 2011
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1
3
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IAEA Nuclear Energy Series
Technical
Reports
Non-HEU Production
Technologies for
Molybdenum-99 and
Technetium-99m
No. NF-T-5.4
I
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VIENNA
ISBN 9789201377104
ISSN 19957807

Non-HEU Production Technologies For Molybdenum-99 and Technetium-99m.

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IAEA Nuclear Energy Series

), which because of its single charge is less tightly

anion on alumina. Modern Tc generators contain alumina

from a low specific activity Mo solution

from alkaline aqueous molybdate solutions have been widely

. The primary column contains

eluted from a generator, usually at room temperature, but at times

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